α-Keto Acids: Acylating Agents in Organic Synthesis - Chemical

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α‑Keto Acids: Acylating Agents in Organic Synthesis Filipe Penteado, Eric F. Lopes, Diego Alves, Gelson Perin, Raquel G. Jacob, and Eder J. Lenardão*

Chem. Rev. Downloaded from pubs.acs.org by UNIV OF LOUISIANA AT LAFAYETTE on 04/16/19. For personal use only.

Laboratório de Síntese Orgânica Limpa - LASOL - CCQFA - Universidade Federal de Pelotas - UFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil ABSTRACT: A significant number of important acyl-transfer reactions, such as direct acylation, ortho acylation, heteroatom acylation, and a diversity of cyclization reactions using the title compound as a key starting material, have been described in recent years. Just like a sleeping beauty, α-oxocarboxylic acids were awakened from a 17-year sleep to become important reagents in classical and new acylation reactions. The greener characteristic of the coproduct formed in reactions using α-keto acid (only CO2), together with its versatility as a building block in catalytic organic synthesis, accredit it as a candidate to green acylating agent, an alternative to acyl chloride, and other acyl-transfer reagents. This review presents the impressive breakthroughs achieved mainly in the past decade in the development of new catalytic reactions for the formation of C−C, C−N, and C−S bonds using α-keto acids.

1). Over the past years, the structural diversity of α-keto acids 1 has greatly increased, with a wide variety of R groups attached to the keto carbonyl. This class of compounds plays a crucial role in the biological system of animals, plants, and bacteria, mainly in processes for supplying energy to cells.1 In this context, the 2-oxopropanoate 2, a pyruvate derivative anion, is the essential metabolite in a process known as Krebs cycle, providing distinct organic species, which can start a series of sequential enzyme-catalyzed reactions to generate adenosine triphosphate (ATP).2 This metabolite acts as an acylating agent in the formation of acetyl-CoA 3 through the pyruvate dehydrogenase-catalyzed decarboxylative acylation of CoA-SH 4, in the presence of NAD+ (Scheme 1A). In addition, acetyl-CoA 3 undergoes a condensation reaction with oxaloacetic acid 5, leading to the citrate 6, a key intermediate in the Krebs cycle (Scheme 1B).2 Pyruvate 2 can also undergo a pyruvate carboxylasecatalyzed condensation reaction with carbonic acid, driven by the hydrolysis of ATP, leading to oxaloacetate dianion 5′, another key intermediate in the Krebs cycle (Scheme 2).2 Due to the biochemical importance of α-keto acids, synthetic methodologies to access them have been emerging since 1835, when Berzelius reported, for the first time, a synthetic approach to access pyruvic acid.3,4 A few reviews

CONTENTS 1. Introduction 2. Classical Methods and Recent Advances in the Synthesis of α-Keto Acids 2.1. Physical Properties of α-Keto Acids 3. α-Keto Acids in Acylation Reactions 3.1. Aryl Acylation 3.1.1. Heteroarene Acylation 3.1.2. Direct Acylation of Aromatic Rings 3.1.3. Ortho-Acylation of Aromatic Rings 3.1.4. Indole Acylation 3.2. Alkene Acylation Reactions 3.2.1. Direct Acylation of Alkenes 3.2.2. Acylarylation of Alkenes 3.3. Alkyne Acylation Reactions 3.3.1. Direct Acylation of Alkynes 3.3.2. Acylarylation of Alkynes 3.4. Heteroatom Acylation Reactions 4. α-Keto Acids in Cyclization Reactions 5. Miscellaneous 6. Conclusions Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

A C G G G G U AC BM BW BW CP CU CU DD DG DO EO EY FA FA FA FA FA FA FB

Figure 1. Generic structure of α-keto acids.

1. INTRODUCTION The α-keto acids or α-oxocarboxylic acids 1 are a class of organic compounds characterized by the presence of a keto group at the α-position of a carboxylic acid function (Figure © XXXX American Chemical Society

Received: December 20, 2018

A

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Scheme 1. Pyruvate Dehydrogenase-Catalyzed Decarboxylative Acylation of CoA-SH

later, this interesting class of compounds was rediscovered by Gooßen and co-workers, who used the α-keto acids in Pd/Cucatalyzed decarboxylative cross-coupling reactions with aryl bromides to prepare ketones.24 Just like a sleeping beauty,25 α-keto acids 1 have recently played an important role in the development of radical acylation reactions for the formation of new C−C, C−N, and C−S bonds, being a greener and versatile alternative to acyl halides, anydrides, and other acylating agents, like carbonyl diimidazole (CDI)26 and thioesters.27 Many of the current methods for acyl transfer employ stoichiometric quantities of activating reagents such as carbodiimides (DCC,28 DIC29), aminium salts (HATU,30 HBTU, 31 TBTU 32 ), and phosphonium-based reagents (BOP,33 PyBOP34), among others, which lead to a large amount of undesirable, toxic wastes (Figure 2). The use of α-keto acids in radical-mediated decarboxylative cross-coupling reactions was reviewed by Duan and coworkers.35 In that nice review, recent works in transitionmetal- and visible-light-catalyzed acylation of alkenes, alkynes, and heteroatoms were discussed. In 2014, Miao and Ge published an account in the Pd-catalyzed cross-coupling of αketo acids and derivatives in acylation reactions.36 More recently, two interesting reviews on the decarboxylation of carboxylic acids in the formation of C−C bonds appeared in the literature.37,38 Herein, we present a comprehensive review covering the plethora of methods using α-keto acids 1 as building blocks to prepare functionalized precursors and complex bioactive molecules. The synthetic versatility of α-keto acids 1 is presented and discussed in condensation and acylation reactions to access a wide range of valuable structures. The main preparative methods currently used to prepare this class of compounds, as well as a brief discussion on their physical properties, are also addressed in this review. For a better discussion and understanding, the range of synthetic methodologies, in both the synthesis and application of α-keto acids as starting material, was divided into five major groups: (i) synthesis and properties of α-keto acids, (ii) α-keto acids in acylation reactions of aryl, heteroaryl, alkenes, and

Scheme 2. Formation of the Oxaloacetate Dianion from Pyruvate

were published in the 20th century, covering preparative methods to access α-keto acids 1.5−9 In 1947, four of the main methods known to prepare α-keto acids 1 at that time were revised by Waters, who also discussed some of their chemical and physical properties.9 In 1983, a comprehensive review was published,10 authored by Cooper and co-workers, covering most of the synthetic and enzymatic methods published until that time to access α-keto acids 1. About 20 general procedures, besides detailed physical and chemical properties of a number of α-keto acids 1, were presented. Basically, these previous reviews were focused on describing synthetic methods to prepare α-keto acids 1 and their physical-chemical properties, with few examples of their, then incipient, synthetic applications. Despite the unquestionable biochemical importance that has been attributed to α-keto acids 1 since the 19th century, the use of this class of compounds as starting materials in organic synthesis started to be considered around the 1930s and 1940s, mainly in esterification and condensation reactions.11,12 Over the following years, until nowadays, several studies on the behavior of α-keto acid 1 in condensation and esterification reactions with N-, O-, and S-based nucleophiles have contributed to elucidate its reactivity as an electrophile in both carbonyl and carboxyl groups, in the construction of a wide range of structures.13−22 A major breakthrough in the chemistry of α-keto acids was the seminal work by Fontana and co-workers,23 who used them in the direct Ag-catalyzed selective radical C2-monoacylation of pyridines. This discovery established the utilization of these compounds as acylating agents, by the formation of an acyl radical species as the key intermediate. After 1991, however, the study of α-keto acids entered a deep sleep. Then, 17 years B

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Figure 2. Reagents and additives for acyl-transfer reactions.

Scheme 3. Preparative Methods to α-Keto Acids

alkynes, (iii) heteroatom acylation, (iv) cyclization reactions, and (v) miscellaneous reactions.

2. CLASSICAL METHODS AND RECENT ADVANCES IN THE SYNTHESIS OF α-KETO ACIDS A large part of the development in the synthesis of α-keto acids was carried out in the first half of the 20th century, with a variety of precursors being applied in different reactions to access a wide scope of derivatives. The reviews published by Waters in 19479 and Cooper in 198310 are pivotal insofar as they covered in detail the state of the art, at that time, of the synthesis of α-keto acids. Even though many approaches to access α-keto acids are found in the literature, probably the most common and usual, mainly to access multigram amounts of products, are those protocols involving the oxidation of C−H and C−C bonds by a strong oxidizing agent. The classical oxidizing agent used in these transformations is KMnO4, first used by Claus and Neukranz in 1891.39 The Csp3−H bond of acetophenone 7a was oxidized under basic conditions (KOH), leading to αphenyl glyoxylic acid 1a (PGA) in 70% yield (Scheme 3A). In 1939, Hurd and co-workers40 reported the use of KMnO4/aq. NaOH as an effective oxidizing medium to convert styrene 8a in PGA 1a in 55% yield (Scheme 3B). Five years later, Oakwood and Weisgerber41 reported a mole-scale synthesis of 1a by the hydrolysis of benzoyl cyanide 9a with aqueous hydrochloric acid (Scheme 3C). Despite that this is a

quite robust methodology, it may take up to 5 days for reaction completion, and the product was isolated in yields from 73 to 77%. Although the precedent methods are robust and have been widely used until these days, they have some limitations, like the use of the strong oxidizing KMnO4 in the presence of strong bases (Scheme 3A,B). In method C, despite the use of a strongly acidic medium, the synthesis of the starting benzoyl C

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Scheme 4. Synthesis of α-Keto Acids from Acetophenone Using SeO2 in Pyridine

Scheme 5. Perfluorinated Oganoselenium-Catalyzed Oxidation of Acetophenone Derivatives with PhIO2

Scheme 6. AZADO/NaNO2-Catalyzed Chemoselective Oxidation of α-Hydroxy Acids

cyanide 9a is not trivial, involving the use of benzoyl chloride and/or HCN.42

The use of SeO2 as oxidizing agent combined with pyridine (Py) in the oxidation of the Csp3−H bond in acetophenone 7a D

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Figure 3. Melting points (mp) of straight-chain and aryl α-keto acids 1.50−61

emerged in the 1960s as an alternative to these methodologies. This milder protocol has been widely used in the last 40 years43−46 to access α-keto acids 1 with a range of appended functionalities. Despite being widespread, the first studies expanding the reaction scope starting from methyl ketones were only published in 2008.47 According to West and co-workers,

there is no apparent electronic effects starting from electronrich and electron-poor acetophenones, leading to the respective products 1 in good to excellent yields. By this procedure, p-chloroacetophenone and p-nitroacetophenone were converted to the respective α-keto acids 1b and 1c in essentially the same yields. From this study, the oxidizing system SeO2/Py has become the most used strategy to prepare E

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Scheme 7. Ag(I)/S2O8−2-Promoted Regioselective Acylation of N-Heteroarenes

α-keto acids 1 to be used as starting material in wide synthetic transformations (Scheme 4). A greener alternative to access α-keto acids 1 was recently developed, as an attempt to circumvent some drawbacks of the classical oxidative methods. For instance, Crich and coworkers48 developed a selenium-catalyzed oxidation of ketones 7 to prepare aryl-substituted glyoxylic acids using iodox-

ybenzene (PhIO2) as the oxidizing agent and fluorous seleninic acid (10 mol %) as the catalyst. By using a biphasic fluorous system, the fluorous phase containing the catalyst could be recovered and reused in new reactions. The method was successfully applied in the synthesis of five different arylsubstituted glyoxylic acids in 89−92% yield after 3 h at room temperature (Scheme 5). F

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Scheme 8. Mechanism of the Ag(I)-Catalyzed Decarboxylative Acylation of N-Heteroarenes

More recently, Shibuya and co-workers49 reported a general method to prepare α-keto acids 1 starting from α-hydroxy acids 10, which were previously prepared by the oxidation of 1,2-diols 11 (Scheme 6). Authors used air as a green oxidant, in the presence of 2-azaadamantane N-oxyl (AZADO)/NaNO2 and MeCN as the solvent. A variety of differently functionalized α-keto acids 1 were prepared in good to excellent yields after 2 h of reaction at room temperature (Scheme 6). As it can be seen in Scheme 6, the method is chemoselective and tolerates a diversity of functional groups, which are sensible to both strong oxidizing agents and strong bases. The possibility of using molecular oxygen as a mild oxidant allows the preparation of highly functionalized α-keto acids 1, including ester, silyl ether, benzyl carbamate, alkene, and alkyne derivatives in very good yields. Besides, β-amino glyoxylic acids 1o and 1p were obtained in very good yields and with minimum racemization.

room temperature, as we have observed their stability for up to six months. Straight-chain α-keto acids present periodicity in melting point values, and as their chain length increases, the physical appearance varies between liquids and solids at room temperature, showing a very similar behavior to fatty acids, as can be seen for 1w−1af in Figure 3. In the literature, there are only a few studies regarding the physical properties connected to the structure of glyoxylic acids.55 From the values of melting point shown in Figure 3, it is possible to infer that straight-chained, aryl- and heteroaryl αketo acids tend to be, in general, solids.

3. α-KETO ACIDS IN ACYLATION REACTIONS 3.1. Aryl Acylation

3.1.1. Heteroarene Acylation. Since the beginning of the 21st century to the 1990s, α-keto acids have been discretely used in a limited number of synthetic transformations. This picture began to change in 1991, when Fontana and coworkers23 reported for the first time the use of α-keto acids 1 as acylating agents in the selective acylation of heteroaromatic bases 12−15. A silver-catalyzed oxidative decarboxylation of αketo acids by (NH4)2S2O8 in a biphasic system (H2O/ CH2Cl2) or in water was used to prepare mono- and diacyl derivatives 16−19 and 16′−19′. The authors settled quinoline 12, pyrazine 13, quinoxaline 14, and 4-substituted pyridines 15 to compare the reactivity and selectivity in mono- and diacylations. PGA 1a (R = C6H5) was the best acyl transfer substrate, leading to the exclusive formation of the monoacylated products in quantitative yields for all the tested substrates. The presence of acid is essential in the reaction, and different selectivity was observed using H2SO4 or CF3CO2H,

2.1. Physical Properties of α-Keto Acids

Most of the α-keto acids 1 are not soluble in water, except those containing alkyl short-chain derivatives, such as glyoxylic 1t, pyruvic 1u, and 2-oxobutyric acid 1v. Long-chain and aryl derivatives present good solubility in a wide range of organic solvents, such as toluene, acetone, 1,4-dioxane, CH2Cl2, DCE, THF, NMP, DMF, DMA, CH3CN, DMSO, ethanol, and diglyme. In some cases, mixtures of H2O and these organic solvents in different ratios are used to access specific reaction conditions. Waters and co-workers9 reviewed that straight-chain and some aryl α-keto acids are slightly unstable under air moisture at room temperature and can be decomposed into aldehydes, carboxylic acid, and oxalic acid. On the other hand, keto acids such as aryl and heteroaryl α-keto acids 1 are quite stable at G

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Scheme 9. NH4I-Catalyzed Electrochemical Decarboxylative Acylation of N-Heteroarenes

with the first favoring the formation of diacylated products 16′−19′ (Scheme 7). The proposed mechanism for the acylation is a redox chain process, involving in the first step the formation of the acyl radical from the α-keto acid 1 (slow step), by the Ag2+ species, which is generated in situ by the persulfate-promoted oxidation of the Ag+ cation. Following, the protonated nitrogenated heterocycle (represented by pyridine 15) reacts with the acyl radical to give the radical-cation A that, after releasing a proton, affords the radical acylated pyridine B. The termination step to form acylated pyridine 19 could involve both reaction of B with Ag2+ to regenerate Ag+ and reaction with persulfate anion, giving radical-anion sulfate SO42−. The higher efficiency of the biphasic system H2O/CH2Cl2 over the aqueous one is attributed to the prevention of the complexation of the silver cation with the nitrogen of the deprotonated base. The organic solvent removes the small amount of heteroaromatic base from the aqueous phase, preventing the complexation with the metal (Scheme 8). As mentioned before, this protocol developed by Fontana and co-workers has opened new horizons in the use of α-keto acids in synthetic organic chemistry, which has been widely explored during the past decade. In the next sections, we will

present the recent developments in the use of α-keto acids in acyl-transfer reactions. In order to overcome problems of polyacylation in the Fontana/Minisci acylation reaction,23 Zeng and co-workers62 have reported, in 2017, an electrocatalytic approach to access monoacylated N-heteroarenes, starting from pyrazines 13, quinoxalines 14, quinolines 12, and pyridines 15 by the reaction with α-keto acids 1. The protocol involves the use of NH4I (15 mol %) as a redox catalyst, playing an important role in the generation of the key acyl radical, in a 0.1 M solution of LiClO4/CH3CN with hexafluoroisopropanol (HFIP) acting as a stabilizing radical species, for 6 h at 70 °C, into a undivided electrochemical cell operating in a constant current electrolysis of 3 mA/cm2, equipped with graphite plates (anode and cathode). Under the optimized reaction conditions, the authors have accessed 22 acylated N-heteroarene derivatives in poor to moderate yields (Scheme 9). Interesting results were obtained using different aromatic and aliphatic α-keto acids 1, to access acylated quinoxalines 18b, 18c, and 18d−f, demonstrating good suitableness, mainly regarding the alkyl αketo acid derivatives. In addition, quinoxalines 14 bearing electron-donating (R1 = OMe) and -withdrawing groups (R1 = CN, Cl, and Br) were well tolerated, affording the derivatives H

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Scheme 10. Mechanism of the Eletrochemical Decarboxylative Acylation of N-Heteroarenes

Scheme 11. Ag(I)-Catalyzed Decarboxylative Acylation of Pyridine-N-Oxide

yield, from an in situ dechlorination of 18l due to the

18a and 18g−j in moderate yields. Quinoxaline substituted with a methyl group (R1 = CH3) on the C2 was acylated in the ortho-position, giving 18k in 44% yield; meanwhile, 2chloroquinoxaline did not endure the reaction conditions, once only the dechlorinated product 18a was isolated in 16%

utilization of an undivided electrochemical cell. Limitations were also found when monosubstituted pyrazines 13 were employed, yielding the desired products 17a and 17d−f I

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Scheme 12. Mechanism of the Ag(I)-Decarboxylative Acylation of Pyridine-N-oxide

Scheme 13. Catalyst-Free Decarboxylative Acylation of Isoquinolines

catalyzed selective C2-monoacylation of pyridine-N-oxides 22 using α-keto acid 1 as an acylating agent. The method involves the use of Ag2CO3 (10 mol %) as the catalyst and K2S2O8 as an oxidizing agent, in a DCM/H2O mixture as the solvent. By this procedure, authors were able to prepare 15 different acylated pyridine-N-oxides 22 after 12 h of reaction at 50 °C in 43− 81% yields (Scheme 11). The best result was obtained starting from 4-methyl-pyridine-N-oxide 22a and 4-chlorophenylglyoxylic acid 1b, affording the respective 2-acylated heteroarene 23a in 81% yield, while 4-trifluoromethylphenylglyoxylic acid 1k reacted with 22a to deliver the expected acylated pyridineN-oxide 23e in only 43% yield. The observed results indicate that electronic effects are not important in the pyridine ring, while some negative influence was observed when the strongly electron-withdrawing CF3 group was present in the α-keto acid counterpart, as in 1k. Authors fixed PGA 1a and tested the acylation reaction of differently substituted pyridine-N-oxides 22, and the obtained results showed that the reaction follows a radical mechanism instead of C−H bond activation.63 For example, 2-methylpyridine N-oxide 22b reacted with 1a under the optimized reaction conditions to afford 75% yield of a mixture of C-2 and C-4 acylation products 23i and 23i′, in around 1:1 ratio.

poorly, while 2,5-dichloropyrazine afforded the acylated product 17g in 65% yield (Scheme 9). Based on cyclic voltammetry studies and several control experiments, as well as based on the literature, a plausible reaction mechanism was disclosed, highlighting the role of the iodine ion and its catalyst feature. A representative mechanism is shown in Scheme 10 for the reaction between pyruvic acid 1u (R = CH3) and pyrazine 13 (R = H). Initially, an acid−base reaction between 1u and 13 occurs, affording the charged species I and II. Then, the combination of the in situ generated I2 and the α-keto carboxylate anion I affords the acyl hypoiodite III, which due to its instability undergoes a quickly homolytic dissociation, giving radical iodine and the aroyloxy radical IV. Once formed, intermediate IV easily undergoes a decarboxylation, giving the key acyl radical V, which reacts with the N-heteroarene cation II to afford the radical cation VI that, after a few protonation and deprotonation steps, yields the desired product 17a. Simultaneously, a cathodic reduction of proton gives molecular hydrogen; meanwhile, anodic oxidation of the iodine ion regenerated I2, requiring only catalytic amounts of iodine (Scheme 10). Similar to what was proposed by Fontana in 1991,23 Muthusubramanian and co-workers63 reported in 2014 the AgJ

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Scheme 14. Ag3PO4-Catalyzed Decarboxylative Acylation of Pyrazine Derivatives

Recently, Wu, Zhao, and co-workers69 have disclosed a Ag(I)-catalyzed decarboxylative coupling of pyrazines 13, similarly to what was proposed by Fontana and Minisci in 1991,23 using α-keto acids 1 as the benzoyl source. The protocol involves the reaction of pyrazine 13 with an excess of the aryl-substituted glyoxylic acid 1 (2 equiv) in the presence of Ag3PO4 (10 mol %) as the catalyst and K2S2O8 (2 equiv) as an oxidizing agent, in a mixture of DCM/H2O (1.4:0.6) as the solvent. The mixture was stirred at 40 °C for 24 h, and a diversity of 19 acylated pyrazines 17 could be accessed in poor to excellent yields. In order to study the reaction scope, authors have initially treated 2,5-dimethylpyrazine with several electron-rich and electron-deficient aryl-substituted glyoxylic acids 1. Regarding those substituted in the para position, electron-donating (R = CH3 and OMe) and electronwithdrawing groups (R = Cl and Br) have demonstrated an excellent suitability, leading to the expected products 17i−j and 17l−m in very good to excellent yields. When the isopropyl group (R = 4-iPr) was present, however, the desired product 17k was obtained in only 40% yield. The reaction efficiency was slightly decreased when meta- and orthosubstituted phenylglyoxylic acids were submitted to the optimal reaction conditions, affording the respective products 17m−p in a range of 43% (17o, R = 3-CF3) to 77% yield (17p, R = 2-CH3). Heteroaromatic 2-thienyl- (1an) and 2furylglyoxylic acid (1am) were also used as substrates, and the respective acylated pyrazines 17r and 17s were obtained in 69% and 27% yields, respectively. 1,2-Disubstituted pyrazines were successfully acylated under the optimal conditions, and the products 17t (R = CH3) and 17u (R = C2H5) were obtained in 56% and 41% yield, respectively. On the other hand, unsubstituted pyrazine 13 and pyridine 15 were not good substrates for the reaction, giving the respective products 17v and 19g in 26% and 45% yields. This lower reactivity was observed also for quinoxaline 14 and quinoline 12, which afforded the acylated products 17w and 16e in moderate yields of 58% and 52%, respectively (Scheme 14).

Accordingly, 2,6-dimethylpyridine N-oxide 23c delivered exclusively the C-4 acylated product 23j in 76% yield. Additionally, no product of acylation was observed in the presence of the radical scavenger TEMPO. Based on these outcomes, the authors have proposed a mechanism involving first the oxidation of Ag(I) to Ag(II) by the persulfate anion, followed by the formation of intermediate I. Then, the elimination of CO2 and RCOCOO− 2 gives acyl radical II and regenerates Ag(I) for a new cycle. A radical reaction between II and the C2−N π bond of 22 generates the cation-radical species III that, in the presence of the sulfate anion radical, is rearomatized to the C2-acylated product 23 (Scheme 12). The C1 benzoyl-isoquinolines are an important class of compounds, widely present in a broad range of natural and synthetic bioactive compounds.64−67 Recently, Singh and coworkers68 reported the selective C1 acylation of isoquinolines 24, using α-keto acid 1 as acylating agent, K2S2O8 (3 equiv) as an oxidizing agent, and water as the solvent. The method is metal- and additive-free, and 14 different 1-acylated isoquinolines 25 were obtained in 32−77% yields by heating the reaction mixture at 100 °C for 6 h. The reaction is negatively influenced by the presence of the strong electron-withdrawing group NO2 in the C-5 of the isoquinoline, and 25j was obtained in a moderate yield of 32%. The optimized reaction conditions were successfully used in the acylation of quinoxaline with PGA 1a, giving 2-benzoylquinoxaline 18c in 50% yield. However, when 4-methylpyridine was subjected to the acylation conditions using PGA 1a, the expected 2-benzoyl-4methylpyridine 19i was obtained in only 30% yield (Scheme 13). The authors have proposed a mechanism with the involvement of the key acyl radical intermediate (like II, in Scheme 12), once the reaction did not occur in the presence of TEMPO. Different from the mechanism proposed by Muthusubramanian,63 the formation of the acyl radical is due only to the presence of K2S2O8 under heating, without metal catalysis. K

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Scheme 15. Mechanism of the Decarboxylative Acylation of Pyrazine Derivatives

Scheme 16. Visible-Light Photocatalyst-Free Acylation of N-Heteroarenes

L

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Scheme 17. Synthesis of Isoquinoline-Based Alkaloids

Scheme 18. Mechanism of the Visible-Light Photocatalyst-Free Acylation of N-Heterocycles

key benzoyl radical intermediate I and releasing CO2 to the reaction medium. Subsequently, the protonated 2,5-dimethylpyrazine II undergoes a radical addition at the C-6, forming the

The proposed mechanism of this Ag(I)-catalyzed decarboxylative coupling is initiated by the oxidative decarboxylation of PGA 1a promoted by the system Ag(I)/S2O8−2, affording the M

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Scheme 19. Nickel- and Cobalt-Catalyzed Decarboxylative Acylation of N-Heterocycles

thiophene derivatives, affording 27i and 27j in 78% and 33% yields, respectively. Aliphatic α-keto acids 1l (R = iBu), 1u (R = CH3), and 1v (R = C2H5) could be used as substrates, yielding their derivatives 27k−m in 52−67% yields. Moreover, the presence of the strong coordinating groups NMe2 and SMe attached to the para-position of the aryl-substituted glyoxylic acid 1 was tolerated in the reaction, and the respective products 27f and 27g were obtained in 64% and 48% yields, respectively. Quinolines 12 and isoquinolines 24 were efficiently acylated under the optimal conditions, also used for the developed reaction, affording the products 16f−h, 25a, and 25b in moderate to very good yields. In addition, 1,10phenanthroline 28 and caffeine 29 could also be modified under this protocol, furnishing the bisacylated 1,10-phenanthroline 30a and acylated caffeine 31a in 66% and 42% yields, respectively. When phthalazine 32 was the substrate, a mixture of the mono- and bisacylated products 33a and 33a′ was obtained in 51% and 19% yields, respectively (Scheme 16, selected examples).

cation radical species III, which is deprotonated to afford the radical intermediate IV. Finally, a Ag(II)-mediated oxidation converts the intermediate IV into the corresponding carbocation, which is converted to the expected product 17h, by the loss of H+ (Scheme 15). Very recently, Wencel-Delord and co-workers70 reported a mild, visible-light-induced acylation of N-heterocycles with αketo acids 1 (2 equiv) in the presence of K2S2O8 (2 equiv) as the oxidizing agent in a mixture of CH3CN/H2O (1:2) as the solvent. The reaction mixture was irradiated by two compact fluorescent lamps (CFLs) (26 W) for 15 h, at room temperature, allowing the synthesis of 34 acylated Nheterocycle derivatives (Scheme 16). In general, quinaldines 26 were demonstrated to be suitable substrates under the optimal reaction conditions, being acylated by aryl-substituted glyoxylic acids 1 bearing both electron-donating and electronwithdrawing groups, yielding the respective products 27a−h in moderate to good yields. Good outcomes were also obtained from heteroaryl-substituted glyoxylic acids, such as indole and N

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Scheme 20. Mechanisms of the Ni- and Co-Catalyzed Decarboxylative Processes

excited to a higher energy level (EDA III*), triggering the homolytic cleavage of K2S2O8 and the formation of SO4•−. Once formed, this radical anion promotes the decarboxylation of PGA 1a, affording the key acyl radical I (Scheme 18, path C). Finally, the protonated quinaldine reacts with the acyl radical I, leading to the formation of the desired acylated product 27a (Scheme 18, functionalization step). Azole derivative ketones 35 and 36 are important structural motifs, widely present in bioactive compounds, including anticancer, antiobesity, and antiulcer drugs.72−79 Looking for more suitable methods to prepare this valuable class of compounds, α-keto acids 1 have been emerging recently as an interesting reagent to access acylated azoles.80,81 Two closely related works were described in 2014 and 2015 by Zhang, Ge, and co-workers80 and Sun, Li, Lu, and coworkers,81 respectively, using Ni(II) and Co(II) catalysis in the decarboxylative C-2 acylation of thiazoles 37 and oxazoles 38. In the first work,80 the authors have used a mixture of the azole 37 or 38 and glyoxylic acid 1 (3.0 equiv) in the presence of Ni(ClO4)2·6H2O (7.5 mol %) as the catalyst and Ag2CO3 (3.0 equiv) as the oxidant agent and benzene as the solvent. A total of 30 2-acylated thiazole 53 and oxazole 36 derivatives were prepared in moderate to excellent yields after stirring the mixture above 170 °C (sealed tube) for 24 h. The protocol proved to be robust and general, working satisfactorily for a diversity of oxazoles 38 and aryl glyoxylic acids 1. The method seems to be insensitive to electronic effects; however, the reaction did not work with ortho-substituted phenyl glyoxylic acids (o-CH3 and o-Cl), indicating a possible steric effect in the reaction. Heteroaromatic 3-thienylglyoxylic acid was converted to the expected 2-acyl benzoxazole 36l in only 39% yield under the optimized conditions. The 2-acylated benzothiazole 35a was obtained in 60% yield by the reaction of 37a with PGA 1a, indicating a lower reactivity of the benzothiazole compared to

The new protocol was applied in the synthesis of natural occurring isoquinoline-based alkaloids pulcheotine 25c and a precursor of liriodenine 25d, starting from the properly substituted isoquinoline 25e. Pulcheotine 25c was easily prepared in 78% yield by the acylation of 24a with 4methoxyphenylglyoxylic acid 1h, after 15 h of reaction at room temperature. In the synthesis of 25e, the direct precursor of liriodenine 25d, 2-bromo-phenylglyoxylic acid 1i, was reacted with isoquinoline 24a under the optimal conditions for 15 h, giving the expected acylated intermediate in 73% yield. The conversion to liriodenine 25d was easily done (45% yield) by a reductive photocyclization (irradiation with a 450 W mercury lamp) with NaBH4 in MeOH at room temperature (Scheme 17).71 To reach a better understanding of the pathway of the formation of the key acyl radical intermediate I, several studies involving UV−vis absorption techniques were performed, and three possible pathways were proposed (Scheme 18). Part of the reactive acyl radical I could be directly generated from PGA 1a through light irradiation in the range of 330−380 nm, forming the excited PGA 1a* that, in the presence of S2O82−, releases CO2 to give the radical I, HSO4−, and the radical anion SO4•− (Scheme 18, path A). Alternatively, electron donor−acceptor (EDA) complexes could be involved in the reaction, which could allow an effective light absorption, necessary to the acyl radical formation. The first hypothesis is the formation of EDA complex II, from the interaction between quinaldine (in this case 2-methylquinoline) and PGA 1a. This complex can absorb energy to be excited to a higher energy state, which in the presence of K2S2O8 enhances the photodecarboxylation of 1a, leading to the generation of the acyl radical I (Scheme 18, path B). A third hypothesis is supported by the formation of the EDA complex III, between the quinaldine and K2S2O8, which absorbs energy and is O

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Scheme 21. Pd-Catalyzed Decarboxylative Acylation of Benzofurans and Benzothiophenes

to the formation of the intermediate I. In the meanwhile, the aryl glyoxylic acid 1 reacts with Ag2CO3 to give the silver intermediate II that reacts then with I to afford the Ni(II) species III. Following, a reductive elimination occurs, delivering the 2-acylated product 35 or 36 and Ni(0). Finally, Ni(0) is oxidized by Ag(I) to Ni(II), restarting the catalytic cycle (Scheme 20, Method A).80 In the Co-catalyzed reaction, the authors have suggested an initial oxidation of Co(II) by Ag(I) to Co(III), which reacts with the heterocycles 37 or 38 in the presence of Ag2CO3 to form the Co(III) intermediate IV, through a C−H bond cleavage. Concomitantly, the aryl glyoxylic acid 1 reacts with Ag2CO3 to form the acyl radical V that, after coupling with intermediate IV, affords the Co(IV) intermediate VI. A reductive elimination of VI affords the 2acylated product 35 or 36 and releases the Co(II) species for a new reaction. The involvement of radical intermediates was proved by the addition of the radical scavenger TEMPO in the reaction media, which caused the complete failure of the reaction (Scheme 20, Method B).81 Two important classes of compounds that have attracted attention in medicinal chemistry are the 3-acyl-benzofurans 39 and the 3-acyl-benzothiophenes 40.82−86 As a part of their efforts in developing a simple and attractive method to prepare this valuable class of compounds, Liu, Li, Lang, and coworkers87 reported, in 2015, the decarboxylative C3 acylation of 3-pyridyl-benzofurans 41 and benzothiophenes 42 through the Pd-catalyzed C−H bond activation. In the reaction starting

the benzoxazole analogue 38a (Scheme 19, Method A). In the work of Sun, Li, Lu, and co-workers,81 they have expanded the reaction to other thiazoles 37, using Co(OAc)2·4H2O (20 mol %) as the catalyst, in the presence of Ag2CO3 (3.0 equiv) as oxidizing agent and 3-fluorobenzotrifluoride (3-F-C6H4CF3) as the solvent. Besides the 2-acylated benzothiazole 35a, obtained in 60% yield, other seven benzothiazole and one thiazole were efficiently coupled with aryl-substituted glyoxylic acids 1 (3.0 equiv), giving the respective 2-acylated products in 41−71% yields after 24 h of reaction at 170 °C. When benzoxazoles and oxazoles were used, however, the best catalyst was Co(ClO4)2· 6H2O (10 mol %), which allowed the preparation of 20 2acylated oxazoles 36 in 53−92% yields. Different from the Ni catalyst coupling discussed before, the authors have observed here that the presence of electron-releasing methyl and methoxy groups in the benzoxazole counterpart 38 diminishes the reactivity, and longer reaction times (up 36 h) were needed to afford the 2-acylated derivatives 36i and 36m in acceptable yields (Scheme 19, Method B). As shown in Scheme 19, both protocols (Ni- and Co-catalyzed) present comparable efficacy in promoting the 2-acylation of oxazoles and thiazoles; however, only aryl glyoxylic acids were used, and the extension to the recalcitrant alkyl glyoxylic acids remains a challenge. The proposed mechanism for both reactions is quite similar and is shown in Scheme 20. For the Ni-catalyzed reactions (Method A), the thiazole 37 or the oxazole 38 first undergoes a C−H bond cleavage, promoted by the Ni(II) species, leading P

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Scheme 22. Reaction Mechanism of the Pd-Catalyzed Decarboxylative Acylation

Scheme 23. Ag(I)-Catalyzed Direct Decarboxylative Acylation of 2H-Indazoles

(7.5/1.5/1.0) as the solvent. After stirring for 21 h at 120 °C, 13 different 3-acylated benzofurans 39 were obtained in 71− 96% yields. There is no obvious electronic effect in the reaction; however, the presence of electron-withdrawing

from 3-pyridyl-benzofurans 41, the best conditions involved the use of 2 equiv of the glyoxylic acid 1 in the presence of Ag2CO3 (2 equiv), K2S2O8 (2 equiv), and Pd(Ph3)4 (10 mol %) as the catalyst in a mixture of 1,4-dioxane/AcOH/DMF Q

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Scheme 24. Reaction Mechanism of the Decarboxylative Acylation of 2H-Indazoles

groups (F, Cl) at the para-position in the phenyl group of the aryl-substituted glyoxylic acid 1 caused a decrease in yields, and the respective products 39d and 39e were obtained in 77% and 71% yields. Heteroaryl 2-thienylglyoxylic acid 1an and 2furylglyoxylic acid 1am were suitable substrates for the reaction, affording the respective 3-acyl-benzofurans 39i and 39j in 74% and 79% yields. The C3 acylation of benzothiophenes 42 was also possible; however, some modifications in the experimental conditions were necessary, like the use of 1 equiv of tetrabutyl ammonium bromide (TBAB) as additive, Ag2O (2 equiv) instead of Ag2CO3, and DMF instead of DMSO in the mixture of solvents. A total of 13 3-acyl-benzothiophenes 40 were prepared in 64−95% yields, with the heteroaryl glyoxylic acid derivatives 40i and 40j being obtained in 64% and 67% yields after 21 h at 120 °C (Scheme 21). The reaction mechanism is very similar to the orthoacylation described in section 3.1.3, with the initial formation of the palladacycle I, by the insertion of the heterocycle 41 or 42 to the coordination sphere of the Pd(II) catalyst. Following, the insertion of the Ag−acyl intermediate II to the catalytic cycle leads to the acylated intermediate III, which through a reductive elimination releases the respective product 39 or 40 and Pd0. Finally, Pd0 is reoxidized to PdII by K2S2O8, for a new catalytic cycle (Scheme 22). Recently, Oh and co-workers88 have reported the first direct acylation of 2H-indazoles 43 with α-keto acid 1 derivatives through a Ag(I)-catalyzed decarboxylative cross-coupling reaction. The best reaction condition consists in stirring a mixture of the 2H-indazole 43 and the α-keto acid 1 (3 equiv) in the presence of AgNO3 (20 mol %) as the catalyst and Na2S2O8 (3 equiv) as the oxidant in a 1:1 mixture of acetone:H2O as the solvent, at room temperature for 24 h. The methodology proved versatile, once 36 different C3-acylated 2H-indazoles 44 were accessed starting from aliphatic and aromatic glyoxylic acids 1 and 2-aryl or 2-alkyl-substituted 2Hindazoles 43. Among the tested substrates, it was not possible to observe any electronic effects caused by substituents at the phenyl ring of the arylglyoxylic acid 1, and electron-rich and electron-poor substrates gave around the same yield of the

respective 3-acylated 2H-indazoles 44. For example, products 44c (R = 4-CH3) and 44e (R = 4-OMe) were obtained, respectively, in 81% and 66% yields, while 44h (R = 4-Cl) and 44j (R = 2-CF3) were formed in 81% and 66% yields, respectively. Aliphatic and heteroaromatic α-keto acid 1 derivatives were suitable substrates in the reaction, and the desired products 44r (R = CH3), 44s (R = nPr), 44t (R = tBu), and 44x (R = 2-thienyl) were obtained in 40%, 74%, 55%, and 51% yields; however, the reaction temperature was increased to 50 °C to give acceptable yields. The reactivity of the 2Hindazoles 43 was markedly influenced by the identity of the pendent group at the N-2, with electron-rich phenyl groups being less reactive compared to unsubstituted or electron-poor ones. The low reactivity was also observed when 2N-alkylsubstituted 2H-indazoles 43 were used as substrates in the reaction with PGA 1a under the optimal conditions. For instance, products 44k (R = 4-CH3) and 44l (R = 4-OMe) were obtained in 61% and 57% yields under 50 °C, while the analogues 44n (R = 4-Cl) and 44o (R = 4-Br) were isolated in 75% and 74% yields in reactions performed at room temperature. Interestingly, the strong electron-withdrawing group CF3 has negatively affected the reaction, and product 44p was isolated in 61% yield at 50 °C. The N-alkylsubstituted derivative 44u (R = nHex) was obtained in only 27% yield after 24 h at 50 °C, while products 44v (R = cyclohexyl) and 44w (R = tBu) were isolated in 25% and 38% yields (reactions at room temperature). 6-Substituted and 5substituted 2H-indazoles 43 were successfully employed in the reaction, affording the desired products 44y (R = 5-F) and 44z (R = 6-CH3) in 75% and 63% yields, respectively (Scheme 23, selected examples). After several control experiments, involving the reaction of 2-phenyl-2H-indazole 43a with PGA 1a, the mechanism depicted in Scheme 24 was proposed. The authors have observed that no reaction occurs in the absence of Na2S2O8 or AgNO3 and that the formation of the expected 3-acylated product 44a is suppressed in the presence of the radical scavenger TEMPO (a 1:1 mixture of DMSO/H2O was used as the solvent). Besides, when 1H-indazole and 1-phenyl-1Hindazole were used instead of 2-phenyl-2H-indazole 44a, no R

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Scheme 25. Ag(I)-Catalyzed Decarboxylative Acylation of Quinoxalin-2(1H)-ones

methylquinoxalin-2(1H)-one 46a. Differently, N-alkyl quinoxaline-2-ones 46 were successfully employed as substrate in the reaction with PGA 1a, giving the desired products 45i−k in moderate to good yields (53−73%), however inferior to that obtained using NH-free quinoxaline-2-one 46b (45l, 85% yield). Additionally, phenyl-disubstituted quinoxaline-2-ones 46 were used as substrates, and the results indicate that the electronic effect on the fused phenyl ring does not affect the reactivity in the formation of products 45m−r, once these were obtained in similar yields of those obtained starting from unsubstituted N-substituted quinoxaline-2-ones 46. A notable exception was the quinoxaline-2-one 46 substituted with the strong electron-withdrawing group NO2 that failed completely in the reaction with PGA 1a under the optimal conditions (Scheme 25, selected examples). When the reaction between NH-free quinoxaline-2-one 46b and PGA 1a was performed in the presence of TEMPO (3 equiv), the expected product 45l was not formed, hinting that a radical mechanism is operating. Then, a proposed mechanism was depicted where the first step is the oxidation of Ag(I) to Ag(II) by K2S2O8. Following, Ag(II) promotes the decarboxylation of PGA 1a to give the acyl radical I that, in the presence of 46b, affords the radical adduct II. Subsequently, a SET from II to Ag(II) gives the cationic intermediate III that, after releasing a proton, affords the product 45l (Scheme 26). The authors have used the new strategy to prepare 3-acyl quinoxalinones 45 as a key step in the synthesis of compound 47, a 3-benzoyl-2-piperazinyl-quinoxaline derivative from a new class of potential antitumor agents.90 Starting from commercial available quinoxalin-2(1H)-one 46b and PGA 1a, compound 45l was prepared in 85% yield as described in Scheme 25. Following, 45l was converted to the 3chloroquinoxaline 48 that, after reaction with 1-phenylpiperazine at 100 °C for 2.5 h, gave the desired compound

radical addition was observed, hinting that the less aromatic quinonoid character of 2H-indazoles 43 is crucial for the success of the reaction. In the mechanism, the first step is the decarboxylative formation of the acyl radical I from 1a by Ag(II), which is generated in situ by Na2S2O8. Then, two competing reactions can occur: a SET to Ag(II) to form the acyl cation II or the reaction with 2-phenyl-2H-indazole 43a, affording the radical intermediate III. In the presence of water from the solvent, cation II forms benzoic acid, while intermediate III is converted by Ag(II) to the cation IV, which rearomatizes to 3-acyl-2H-indazole 44a by loss of a proton (Scheme 24). In 2017, Wang, Hu, and co-workers89 reported a general protocol to access 3-acyl quinoxaline-2(1H)-ones 45 through the Ag(I)-catalyzed decarboxylative acylation of quinoxaline-2ones 46, using α-keto acids 1 as acylating agents. The optimal conditions involved the stirring of a mixture of quinoxaline-2one 46 and the α-keto acid 1 (2 equiv) in the presence of AgNO3 (10 mol %) as the catalyst and K2S2O8 (2 equiv) as the oxidant, in a 1:1 (v/v) mixture of MeCN and water as the solvent, at 100 °C for 3 h. The desired products 45 were generally afforded in reasonable to good yields starting from aromatic and heteroaromatic glyoxylic acids 1 and differently substituted quinoxaline-2-ones 46. The presence of electrondonor groups in the aryl-substituted glyoxylic acid 1 positively affects the reaction, compared to the electron-withdrawing ones. For instance, products 45d (R = 4-CH3) and 45e (R = 4OMe) were obtained in 80% and 86% yields, while 45f (R = 4Cl) and 45g (R = 4-Br) were isolated in 65% and 60% yields, respectively. Despite the modest yields, pyruvic acid 1u was a suitable substrate for the reaction, giving the 3-acyl quinoxaline-2(1H)-ones 45s (R = CH3) and 45t (R = CH2CO2Et) in 36% and 34% yields. The heteroaromatic 2-thienylglyoxylic acid 1an served as a good acyl transfer moiety in the reaction, affording product 45u in 53% yield after reaction with 1S

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yield, while p-methoxyphenyl glyoxylic acid (R = 4-OMe) and p-nitrophenyl glyoxylic acid gave the products 49c and 49f in 21% and 46% yields, respectively. The robustness of the protocol was shown in the use of aliphatic and heteroaromatic glyoxylic acids, and products 49g (R = CH3), 49h (R = nPr), and 49i (R = 3-thienyl) were isolated in 52%, 48%, and 56% yields, respectively. The presence of substituents at the orthoposition in the phenyl ring negatively affected the reaction, giving the respective product 49h in only 8% yield, probably due to steric hindrance. Regarding the N-phenyl-substituted pyrazolones 50, the presence of an electron-donor group at the pendent phenyl ring positively affected the reaction, while electron-withdrawing substituents significatively reduced the reactivity of the substrate. For example, product 49j (R = 4OMe) was obtained in 87% yield, while the electron-poor derivatives 49l (R = 4-NO2) and 49m (R = 3-SO2NH2) were isolated in 21% and 38% yields, respectively. Good results were obtained using other N-alkyl-substituted pyrazolones 50, including benzyl and allyl derivatives, affording the products 49q (R = Bn) and 49r (R = allyl) in 29% and 60% yields (Scheme 28, selected examples). While studying the reaction mechanism, the authors have observed that the presence of a radical scavenger in the reaction medium suppressed the reaction, although not totally, indicating that radical intermediates are involved. Besides, the use of other benzoyl precursors under the optimal conditions failed in affording the 4-acylated product, and no kinetic isotope effect (KIE) was observed. These findings, together with the higher reactivity showed by electron-poor arylsubstituted glyoxylic acids 1, were used to support the involvement of an acyl copper species (RCO-Cu) as an intermediate in the reaction. Two plausible reaction pathways were proposed by the authors (Scheme 29). The first one (Pathway A) involves initially a Cu(II)-promoted C−H activation of the pyrazolone 50, giving the Cu(II)−pyrazolone complex I, which undergoes a protonolysis by the α-keto acid 1, to afford the acyl−Cu(II) complex II. Subsequently, a SET promoted by the sulfate radical anion oxidizes the Cu(II) complex II to the highly unstable Cu(III) intermediate III, which is quickly reduced to a Cu(I) species, releasing the desired product 49 to the reaction medium, by a reductive elimination pathway. Finally the Cu(I) species is reoxidized to Cu(II) by a sulfate radical anion in the presence of AcOH. In the case of less reactive pyrazolones 50, such as steric hindered

Scheme 26. Reaction Mechanism of the Decarboxylative Acylation of Quinoxalin-2(1H)-ones

47 in an overall yield of 45%, which is double that previously reported (Scheme 27). Recently, Yotphan and co-workers91 have disclosed a Cu(II)/persulfate-promoted synthesis of 4-acylpyrazolones 49 through an oxidative decarboxylative acylation of pyrazolones 50 with α-keto acid 1 as the acyl source. In an optimized procedure, a mixture of the N-substituted pyrazolone 50 and the α-keto acid 1 (1.5 equiv) is stirred for 4−16 h in the presence of Cu(OAc)2 (50 mol %) and K2S2O8 (1.5 equiv), using a 1:1 mixture of MeOH and H2O as the solvent at 60 °C. Under these conditions, 29 differently substituted 4-acylated pyrazolones 49 were accessed in moderate to excellent yields. A study regarding the effect of substituents on the phenyl ring of the aryl-substituted glyoxylic acid demonstrated that the presence of substituents reduces the reactivity compared to the unsubstituted PGA 1a. There is not a clear electronic effect; however, strong electron-donor and strong electron-withdrawing groups were worst in affording the respective 4-acylated pyrazolones. For example, PGA 1a reacted with 1,5-dimethyl-2-phenyl-1,2-dihydro-3Hpyrazol-3-one 50a to afford the respective product 49a in 90%

Scheme 27. Application in the Synthesis of Potential Anticancer Agents

T

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Scheme 28. Cu(II)-Catalyzed Decarboxylative Acylation of N-Substituted Pyrazolones

simple protocol, the starting α-keto acid potassium salts 2 are readily accessible, and easy-to-handle and stoichiometric amounts of organometallic reagents are not required. However, a high reaction temperature (170 °C), long reaction times, and the need to use two different ligands are some limitations of this method. Inspired by this pioneering work of Gooβen and co-workers in the acylation of aryl bromides 52, an improvement was described by Ji and co-workers,92 in 2014. By using the bicatalytic system Cu/Pd and aryl iodides 53 instead of aryl bromides 52, they were able to prepare the desired ketones 51 in the absence of P-based and N-based ligands. Different copper and palladium salts were tested, and the best results were obtained using CuI/PdI2 (5 mol %) in NMP as the solvent at 120 °C for 3 h. By this procedure, authors have studied a wide reaction scope, and 27 unsymmetrical ketones 51 were obtained in 72−93% yields (Scheme 31). A bicyclic mechanism was proposed to be involved in both procedures, according to the authors.24,92 In one cycle, the copper salt plays the important role of promoting the decarboxylation of the α-keto acid potassium salt 2, through the intermediate I that, by elimination of CO2, forms in situ the stable copper complex II. The other catalytic cycle involves the well-described oxidative addition of palladium(0) to aryl halides 52 or 53, leading to the intermediate III. Following, intermediates II and III react by a transmetalation reaction, leading to the intermediate IV and regenerating the copper salt in the reaction media. Finally, by a reductive elimination, the

and electron-poor ones, an alternative reaction mechanism could be operating (Pathway B). Initially, the Cu(II) catalyst reacts with the α-keto acid 1, giving the intermediate IV, which is quickly decarboxylated to the intermediate V. Subsequently, an insertion of the pyrazolone 50, in the presence of the sulfate anion radical, affords the intermediate VI through a SET process. Finally, a reductive elimination occurs to give the desired product 49 and a Cu(I) species, which is reoxidized to the initial Cu(II) catalyst, in order to initiate a new reaction cycle (Scheme 29). 3.1.2. Direct Acylation of Aromatic Rings. Only 17 years after Fontana’s work, a long period without any broad and deep study on the behavior of α-keto acids and their derivatives in acylation reactions had passed until the work from Gooβen and co-workers,24 which performed a general study on the synthesis of unsymmetrical ketones 51 using αketo acids. Twenty-six differently substituted unsymmetrical ketones 51 were prepared in 5−99% yields after 16−36 h of reaction at 170 °C, by the cross-coupling reaction of α-keto acid potassium salts 2 and aryl bromides 52. The reaction was catalyzed by Cu/Pd, in the presence of P-(o-Tol)3 and 1,10phenanthroline as ligands and using a mixture of NMP/ quinoline (3:1) as the solvent (Scheme 30). This protocol is a versatile approach to access a wide scope of unsymmetrical ketones 51, with most of the products being obtained in good to excellent yields. One exception was the ketone 51h derivative from mesitylglyoxylic acid, obtained only in 5% yield, probably due to the bulky mesityl group that makes the approach of the aryl counterpart difficult. Besides a U

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Scheme 29. Possible Reaction Pathways of the Cu(II)-Catalyzed Decarboxylative Acylation

iridium polypyridyl complex [IrIII] and nickel catalysts ([NiII]) occurs (Scheme 33).96 By this procedure, 26 unsymmetrical ketones 51 were prepared in good to excellent yields. Starting from 1-bromo-2methylprop-1-ene 54 and bromocyclopentane 55, vinyl ketone 51p and dialkyl ketone 51q were obtained in 73% and 88% yields, respectively. To show the applicability of the protocol, the authors prepared the properly substituted α-keto acid 1ap and reacted it with 4-chloro-iodobenzene 53a to obtain, after 96 h, 71% yield of fenofibrate 56, a worldwide marketed cholesterol-modulating drug of the fibrate class (Scheme 34). The α-keto acid 1ap was prepared in 47% yield from the methyl aryl ketone 7b using the SeO2/Py system, developed by West and co-workers.47

desired product 51 is formed, and the palladium catalyst is regenerated to start a new catalytic cycle (Scheme 32). Throughout 2014 and 2015, MacMillan and co-workers93−95 have published three papers that opened new possibilities in the decarboxylative acylation reactions. In these important works, visible-light photoredox decarboxylation reactions were shown to be an excellent synthetic tool to promote the acylation of Csp3 and Csp2, by the formation of the key intermediate acyl radical from carboxylic acids. In 2015, MacMillan has expanded these studies from carboxylic acids to α-keto acids, using aromatic and aliphatic derivatives of α-keto acids 1, including pyruvic acid 1u, in the direct acylation of aryl halides 52 or 53. In this reaction, a synergistic effect of visible-light-mediated photoredox using an V

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Scheme 30. Pd/Cu-Catalyzed Decarboxylative Cross-Coupling of α-Oxocarboxylates and Aryl Bromides

Scheme 31. Pd/Cu-Catalyzed Decarboxylative Cross-Coupling of α-Oxocarboxylates and Aryl Iodides

and potassium oxalate monoamides 57, respectively, leading to the formation of unsymmetrical ketones 51 and amides 58. The authors took advantage of the synergistic effect of the iridium visible-light photoredox- and palladium-catalyzed activation of the aryl halides. By this method, 23 different unsymmetrical ketones 51 and 13 amides 58 were obtained in 10−97% yield using 36 W blue LED at 25 °C during 20 h. The method presents an excellent functional-group compatibility, demonstrated by the synthesis of the steroidal ketone 59, an analogue of estradiol, which was obtained in 75% yield starting from iodide 53b and pyruvic acid 1u under the same reaction conditions (Scheme 35). Transition-metal-catalyzed cross-coupling reactions for C−C bond formation have emerged in the last century as one of the most important and studied topics in organic synthesis. Reactions like Heck, Sonogashira, Negishi, Stille, Suzuki− Miyaura, and Buchwald−Hartwig are widely used nowadays in the synthesis of many biologically important molecules.98−100 Inspired by the decarboxylative cross-coupling reaction of carboxylic acids with activated and nonactivated arenes described by Gooβen,101−104 Ge and co-workers105 reported in 2011 the decarboxylative Pd-catalyzed cross-coupling of potassium aryltrifluoroborates 60 with α-keto acids 1, using K2S2O8 (2 equiv) as an oxidizing agent and a mixture of DMSO/H2O as the solvent. By this procedure, 30 differently

Scheme 32. General Catalytic Cycle of the Pd/Cu-Catalyzed Cross-Coupling of α-Oxocarboxylates 2 and Aryl Halides24,92

In the same year, Shang, Fu, and co-workers97 published a closely related work using the same iridium(III) photoredox catalyst [Ir{dF(CF3)ppy}2(dtbbpy)]PF6 [IrIII], but Pd-catalyzed aryl halide activation instead of the [NiII] one. The methodology was successfully extended to the direct acylation and amidation of aryl halides 52 and 53 with α-keto acids 1 W

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Scheme 33. Merging Photoredox and Ni(II) Catalysis in the Synthesis of Ketones from α-Keto Acids

Scheme 34. Synthetic Applications of the Metallaphotoredox Decarboxylative Acylation

substituted unsymmetrical ketones 51 were prepared in 41− 98% yields at room temperature after 3 h of reaction (Scheme 36). A detailed study regarding the substitution in both glyoxylic acids 1 and trifluoroborates 60 was performed, and some interesting findings were highlighted. For example, the presence of electron-donating substituents and halogens in the aromatic ring of the aryl glyoxylic acid afforded the best

yields of the unsymmetrical ketones 51. The reaction works well with aliphatic α-keto acids, and 2-methyl-1-phenylpropan1-one 51z was obtained in 83% yield from potassium phenyltrifluoroborate 60a and 3-methyl-2-oxobutanoic acid. Even the sterically hindered mesitylglyoxylic acid, which failed completely in the reaction under the Gooβen conditions [Pd(0)/Cu(I)],24 reacted with 60a, giving the respective mesityl ketone 51y in 70% yield. The compatibility of X

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Scheme 35. Merging Photoredox and Pd(II) Catalysis in the Decarboxylative Acylation of Aryl Halides

Inspired by the Pd(II)-catalyzed cross-coupling between potassium aryltrifluoroborates 60 and α-keto acids 1, reported by Ge in 2011,105 Chang and co-workers106 have recently demonstrated the ability of Ag(I) species to play a catalytic role in this transformation. The protocol involves the crosscoupling between α-keto acid potassium salts 2 and potassium aryltrifluoroborates 60, in the presence of AgNO3 (5 mol %) as a catalyst and K2S2O8 as the oxidant, using H2O as the solvent at room temperature for 1 h. The optimized methodology

substituted potassium aryltrifluoroborates 60 was evaluated and showed that electron-rich substrates like p-tolylglyoxylic acid 1ag and p-methoxyphenylglyoxylic acid 1h are more reactive with respect to the electron-poor ones, giving the respective ketones 51a−b in 95 and 82% yields after 3 h at room temperature under the optimized conditions. On the other hand, electron-poor aryltrifluoroborates and o-substituted ones afforded lower yields of the desired products 51r (41%), 51w (41%), and 51aa (54%) (Scheme 36). Y

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Scheme 36. Pd(II)-Catalyzed Decarboxylative Coupling between α-Keto Acids and Aryltrifluoroborates

Scheme 37. Ag(I)-Catalyzed Decarboxylative Coupling between α-Keto Acids and Aryltrifluoroborates

showed to be compatible with a range of aryltrifluoroborates 60 bearing electron-releasing and electron-withdrawing groups in para- or meta-positions, yielding the respective products 51 in very good to excellent yields. Aryltrifluoroborates 60 with substituents at the ortho-position have also been demonstrated to be suitable substrates in the reaction. However, due to steric effects, the yields of the respective products 51ah and 51ai were reduced to 77% and 79%, respectively. In addition,

polyfluorinated bisaryl ketones 51al−an could be synthesized in moderate to good yields (62−71%). Ge and co-workers have effectively and nicely explored these fluorinated compounds, demonstrating the broad applicability of the methodology, once these compounds are of great interest in materials science due to their physicochemical properties (Scheme 37, selected examples). Z

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Scheme 38. Synthetic Application of the Ag(I)-Catalyzed Decarboxylative Acylation of Aryltrifluoroborates

Scheme 39. Pd(II)-Catalyzed Ligand-Free Decarboxylative Coupling of α-Keto Acids and Aryl Diazonium Tetrafluoroborates

the catalyst and (NH4)2S2O8 (2 equiv) as the oxidant in DMF as the solvent under argon atmosphere. Under the optimal reaction conditions, a diversity of 37 unsymmetrical diaryl ketones 51 were obtained in moderate to excellent reaction yield after 10 to 13 h at 90 °C. The authors have performed an exaustive study on the reaction scope, using several aromatic αketo acids 1 and aryl diazonium tetrafluoroborate salts 64 substituted with electron-donor and electron-withdrawing groups. In a general way, it was observed that the presence of electron-withdrawing groups negatively affects the reaction, both regarding the aryl-substituted glyoxylic acid 1 and the tetrafluoroborate 64. For example, electron-rich 4-methyl-, 4ethyl-, and 4-methoxyphenylglyoxylic acids 1 reacted with benzenediazonium tetrafluoroborate 64a under the optimal conditions to give, after 10 h of reaction, the respective diaryl ketones 51a (R = 4-CH3), 51ao (R = 4-C2H5), and 51b (R =

The optimal reaction conditions were successfully applied in the synthesis of chalcones 61 by the decarboxylative crosscoupling reaction between α-keto acid potassium salts 2 and potassium (E)-styryl trifluoroborate 62a. Electron-rich pmethoxyphenyl- and electron-deficient p-chlorophenyl oxocarboylates 2h and 2b were converted to the respective chalcones 61a and 61b in 88% and 83% yields after 1 h of reaction (Scheme 38A). When o-hydroxyl glyoxylate 2aq reacted with ethenyl trifluoroborate 62b, 4H-chromen-4-one 63 was obtained in 52% yield (Scheme 38B). Recently, Ranu and co-workers107 have disclosed a useful methodology to construct unsymmetrical diaryl ketones 51 through the Pd(II)-catalyzed decarboxylative coupling between α-keto acids 1 and aryl diazonium tetrafluoroborate 64. The reactions were conducted using 2 equiv of the aryl-substituted glyoxylic acid 1 in the presence of Pd(PhCN)2Cl2 (5 mol %) as AA

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Scheme 40. Mechanism of the Pd(II)-Catalyzed Synthesis of Unsymmetrical Ketones

Scheme 41. Ag(I)-Catalyzed Decarboxylative Acylation of Arylboronic Acids

fully acetylated with PGA 1a, and the respective diaryl ketone 51aq was isolated in 69% yield. The applicability of this protocol, mainly envisioning some industrial application, was demonstrated by the authors in the synthesis of 51b in a 10 mmol scale. Using the optimal conditions, the expected product was obtained in 63% yield (1.34 mmol, 1.33 g) (Scheme 39, selected examples). Several control experiments were performed aiming to unveil the reaction mechanism, including performing the reaction in the presence of TEMPO and the use of UV and EPR analyses. Together with preview reports insights, the collected information was used to propose a reasonable mechanism for the acylation reaction. Initially, a decarboxylative oxidation of the α-keto acid 1a affords the benzoyl radical intermediate I, which reacts with the Pd(II) catalyst, giving the Pd(III) intermediate II. Following, through an oxidative process, the substrate 64c is coordinated to the palladium coordination sphere, forming the Pd(IV) inter-

4-OMe) in a narrow range of 80−81% yields; meanwhile, the electron-poor derivatives 51aj (R = 4-Br) and 51ai (R = 4CN) were isolated in 72% and 66% yields, respectively. Satisfactorily, the protocol was not sensitive to steric hindrance effects in the α-keto acids 1, once o-tolylglyoxylic acid 1 afforded the product 51ah in 71% yield, while the heteroaromatic derivative 2-thienylglyoxylic acid 1an reacted with 64a to give the product 51ar in 88% yield. Benzenediazonium tetrafluoroborates 64 bearing one or more substituents in para-, meta-, and ortho-positions were suitable substrates for the reaction, affording the respective products 51 in a range of 63% to 91% yields. As mentioned before, the presence of strong electron-withdrawing groups decreased the reactivity of the substrate, affording the respective products 51i (R = 4-CN), 51ad (R = 4-NO2), 51as (R = 3-CN), and 51ak (R = 2-NO2) in a range of 63%− 77% yields. Additionally, the highly sterically hindered 2,6dimethylbenzenediazonium tetrafluoroborate 64b was successAB

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Scheme 42. Decarboxylative Acylation over Arylation in the Synthesis of Fluorenone

Scheme 43. Consecutive Ag(I)-Catalyzed Acylation and Pd(II) Arylation

mediate III, which through a reductive elimination pathway is regenerated to Pd(II), in order to initiate a new catalytic cycle, releasing the coupling product 51b to reaction medium (Scheme 40). The versatility of aryl-substituted glyoxylic acids in decarboxylative acylation reactions was explored by Qi and co-workers108 in the silver-catalyzed decarboxylative coupling with arylboronic acids 65 as an alternative route to access unsymmetrical ketones 51 in good to excellent yields (69− 95%). In a typical procedure, the reagents were stirred at 60 °C for 1 h in the presence of a catalytic amount of Ag2CO3 (10 mol %) and CH3CN as the solvent. The method showed to be general and efficient for a variety of α-keto acids, with excellent outcomes for electron-rich, electron-poor, and sterically hindered aryl-substituted glyoxylic acids 1 (Scheme 41). Regarding the boronic acid counterparts, a good functional group tolerance was observed, including free amine and hydroxyl groups, affording the respective diaryl ketones 51s and 51av in 77% and 72% yields. The authors have designed an experiment to verify the preference of the decarboxylative acylation over the decarboxylative arylation, in the reaction of substrate 1ar with phenylboronic acid 65a under the conditions of Scheme 42. The only product obtained was the ketone 51aw, obtained by the decarboxylative acylation, in 75% yield (Scheme 42A). The authors took advantage of this difference in reactivity in the synthesis of fluorenone 66, obtained in a two-step procedure. In the first step, compound 1as and phenylboronic acid 65a reacted leading to the ketone 51ax, which was directly submitted to an oxidative cyclization reaction, promoted by the addition of K2S2O8, to deliver fluorenone 66 in 62% yield (Scheme 42B). The fluorenone scaffold is present in a number of natural and synthetic bioactive compounds with important pharmacological activities, including anticancer, anti-HIV-1, and antioxidant.109

In the same work, the authors applied the developed methodology in the domino reaction using a sequential Agcatalyzed decarboxylative acylation and a Pd-catalyzed Suzuki− Miyaura cross-coupling sequence, starting from 4-Br-PGA 1j and phenylboronic acid 65a. The resulting 4-bromobenzophenone 51aj was directly reacted with another equiv of phenylboronic acid 65a, now in the presence of a catalytic amount of Pd(OAc)2, giving the desired 4-phenylbenzophenone 51ay in an overall yield of 87% (Scheme 43). 3.1.3. Ortho-Acylation of Aromatic Rings. Over the past decade, plenty of methodologies for transition-metal-catalyzed cross-coupling reactions were developed to access unsymmetrical diaryl ketones 51,93 and these compounds are important structural motifs found in natural products and biologically active molecules.110,111 Traditionally, general cross-coupling methodologies require prefunctionalization of coupling partners with expensive and moisture-sensitive organometallic reagents, which usually leads to stoichiometric formation of side products. Thus, the development of transition-metal-catalyzed cross-couplings directed by electronic effects has become an important approach to circumvent this problem.112−116 Different directing groups have been studied to promote the ortho-C−H bond activation reactions, such as pyridines,117,118 oximes,119,120 acetanilides,121−123 indoles,124 and amides.125,126 Aldehydes and carboxylic acids are widely used as acyl transfer groups in such protocols. In addition to the wide application of α-keto acids 1 in metalcatalyzed direct aryl acylation reactions (described above), metal-catalyzed ortho-aryl acylation reactions have become an interesting field for application of PGA 1a and its derivatives. 3.1.3.1. N-Heterocycles as Directing Groups in oAcylation Reactions. Encouraged by the discoveries of Gooβen,101−104 Li and Ge have applied for the first time PGA 1a and its derivatives in the Pd-catalyzed acylation of unactivated arenes.127 In this unprecedented reaction, 2phenylpyridine 67 and derivatives were acylated via a C−H AC

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Scheme 44. Pd(II)-Catalyzed Ag(I)/S2O8−2-Assisted ortho-Acylation of 2-Phenylpyridines

bond activation, assisted by the system Ag+/S2O8−2. An exhaustive study on the generality of the reaction was performed, and 30 different diaryl ketones 51 were prepared in 37−95% yields after 12−16 h of reaction at 120 °C. A mixture of 1,4-dioxane, AcOH, and DMSO was used as the solvent, and Pd(PhCN)2Cl2 (10 mol %) was the best catalyst (Scheme 44). As it can be seen in Scheme 44, the method is general, and equally good results were obtained for electron-rich and electron-poor pyridyl arenes 67 and aryl-substituted glyoxylic acids 1. The sterically hindered mesitylglyoxylic and 4-methyl2-oxopentanoic acids are less reactive, requiring a longer reaction time (16 h) and the use of Ag2O (3 equiv) instead of Ag2CO3 (2 equiv) to afford the diaryl ketone 51bh and the isopentyl aryl ketone 51bi in 37% and 59% yields, respectively. Regarding the arene counterpart, diaryl ketone 51bo, derived from benzo[h]quinoline, was obtained in excellent yield (95%), while ketones 51bm, 51bs, and 51bv, substituted with the strong electron-withdrawing group CF3, were obtained in moderate yields (56−77%). In the case of 51bs, a reaction time of 16 h was necessary, due to the low reactivity of the arene precursor. A similar lower reactivity was observed when a dihydrooxazole group was in the place of the pyridyl one, as in ketone 51bp, which was obtained in only 41% yield after 16 h of reaction (Scheme 44). In this work, authors did not speculate on the mechanism of the reaction.

A closely related work was described in 2013 by Zhang and co-workers, except that they used aryloxypiridines 68 instead 2-arylpiridines 67 as arenes to promote the ortho-acylation.128 The authors observed that if Ag2O is used in the place of Ag2CO3 the amount of silver salt was halved to 1 equiv, while the yields of the respective diaryl ketones was 40−81%. The method was restricted to aryl- and heteroaryl-substituted glyoxylic acids 1 and was not applied to alkyl-substituted oxoacids (Scheme 45). Slightly higher yields were obtained when electron-rich 2-aryloxypyridines 68 were used as substrates, while the electronic effects were not clearly observed in the α-keto acid counterpart, except for the 3CF3 substituted that reacted with 2-phenoxy-pyridine 68a to deliver the desired diaryl ketone 51cb in 52% yield. Similar modest yields were observed using 2-thienyl glyoxylic acid 1an and 2-naphthyl glyoxylic acid 1at, with the respective diaryl ketones 51cd and 51cf being obtained in 40% and 41% yields, respectively. The directing group pyridine was easily removed in the ketone 51az, affording the useful 2-hydroxydiaryl ketone 51cp in 82% yield, after a simple and robust procedure (Scheme 45). Aiming to clarify the mechanism of the reaction, control experiments were conducted using the radical scavengers TEMPO and 1,1-diphenylethylene, and the desired product 51bw was still obtained in 67% and 56% yields, respectively. Besides, the intermediate 2-phenoxy-pyridine palladacycle I, once isolated (its structure was confirmed by X-ray analysis), AD

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Scheme 45. Pd(II)-Catalyzed Ag(I)/S2O8−2-Assisted ortho-Acylation of 2-Aryloxypyridine

glyoxylic acid 1. The methodology has demonstrated a good tolerance to susbtituents, both in the phenyl glyoxylic acid 1 and in the pendent phenyl ring of pyiridine 67, with the respective products 51 being obtained in moderate to very good yields. An important feature that should be highlighted is that the product 51az, derived from 2-phenylpyridine 67a and PGA 1a, could be obtained in a gram scale (∼1.15 g) in 68% yield, showing the usefulnes of this protocol. The reaction seems to be equally affected by the presence of substituents at the α-keto acid counterpart 1, and there is no clear electronic effect in the reactivity. For instance, unsubstituted diaryl ketone 51az (R = H) was obtained in 76% yield under the optimal conditions, while the electron-rich product 51bb (R = 4-OMe) was isolated in 60% yield and the electron-poor derivative 51cq (R = 4-CF3) was isolated in 57% yield. Satisfactory results were observed starting from orthosubstituted, disubstituted, and aliphatic keto acids 1, affording the desired products in moderate to very good yields. No steric effect was observed starting from the 2,4-dimethylphenyl glyoxylic acid, which afforded the respective product after reaction with 2-phenylpyridine 67a in 70% yield. The recalcitrant isobutylglyoxylic acid 1l was a good substrate in

was able to undergo the reaction with PGA 1a (2 equiv) in the absence of Ag2O and K2S2O8, delivering 51bw in 75% yield. The mechanism depicted in Scheme 46 was proposed for this Pd-catalyzed cross-coupling, with no free radical involved in the reaction. The first step of the reaction is the o-palladation of the 2-phenoxy-pyridine 68a, forming the intermediate I. Then, I subsequently suffers an anion exchange with PGA 1a to afford the intermediate II that, by elimination of CO2, delivers the desired o-acylated product 51bw and Pd(0), for a new catalytic cycle (Scheme 46). In 2017, Jana and co-workers129 have disclosed a mild Pdcatalyzed decarboxylative ortho-acylation of 2-phenylpyridine 67, using PGA 1a and its derivatives as the acyl source. This protocol has circumvented some drawbacks found in the method developed by Li and Ge,127 which uses high temperatures and stoichiometric amounts of Ag(I) salts. In a typical procedure, a mixture of 2-phenylpyridine 67 and α-keto acid 1 (1.5 equiv) in the presence of Pd(OAc)2 (10 mol %) as the catalyst and K2S2O8 (2 equiv) as the oxidant in acetonitrile as the solvent is stirred at room temperature for 16 h under N2 atmosphere. This protocol allowed accessing 24 acylated 2phenylpyridines 51, including one derived from aliphatic AE

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Scheme 46. Mechanism of the Pd(II)-Catalyzed o-Acylation of 2-Aryloxypyridines

glyoxylic acids, with pyruvic and 3-methyl-2-oxobutanoic acids reacting under the optimized conditions to afford the respective 2-phenyl-benzoxazinones 51lm and 51ln in 47% and 54% yields, respectively. Heteroaryl-substituted glyoxylic acids (furyl and thienyl derivatives) afforded the respective oacylated 2-phenyl-benzoxazinones 51lo and 51lp in 57% and 63% yields, while 2-thienyl-benzoxazinone delivered the respective 3-acyl-thienyl-benzoxazinone 51lq in 37% yield. An overview on the electronic effects caused by the substituent groups in the aromatic ring of the substrates shows that electron-releasing groups in the phenylglyoxylic acid 1 positively affect the reaction (e.g., products 51la−lb), while electron-withdrawing ones render moderate yields of the respective monoacylated 2-phenyl-benzoxazinones (e.g., 51lc− le). With respect to the 2-phenyl-benzoxazinone counterpart 69, it was not possible to infer about any electronic effect caused by the substituents; however, generally lower yields were obtained starting from substituted benzoxazinones compared to the unsubstituted one (compare, e.g., 51lf vs 51lg−li). When meta-substituted (F, Me, OMe) 2-arylbenzoxazinones 69 were used, the acylation occurred preferentially at the N-directed position (products 51ls and 51lu−lv), with minor amounts of the O-directed products 51′ being observed, in overall yields of 66−83%. Using m-chlorophenyl-benzoxazinone as the substrate, the N-directed monoacylated derivative 51lt was the only product obtained in 68% yield (Scheme 49). Authors have observed that when AgOTf is used instead of AgNO3 in the presence of a larger excess of α-keto acids 1 (4 equiv) bisacylated benzoxazinones 70 could be obtained in 61−81% yields after 24 h of reaction at 60 °C (Scheme 50). The authors have observed that the reaction proceeds even in the presence of the radical scavenger TEMPO, indicating

the reaction, giving the unsymmetrical diaryl ketone 51bi in 71% yield. 2-Phenylpyrimidine was also used as a substrate in the reaction, and the expected ketone 51cv was obtained in 63% yield, together with a small amount of the diacylated product, in 26% yield (Scheme 47, selected examples). The same approach was successfully extended to 2-oxo-2-phenylacetaldehydes and benzaldehydes as acyl transfer agents. In the case of the aromatic aldehydes, aq. TBHP (3 equiv) was used as the oxidant, and the reaction time had to be extended to 36 h. Several control experiments were performed to investigate the possible mechanism of the reaction, as shown in Scheme 48. First, the pyridine-assisted cyclopalladation of 2-phenylpyridine 67a with electrophilic Pd(II) affords the fivemembered palladacycle I. In parallel, the decarboxylation of PGA 1a promoted by K2S2O8 generates the acyl radical II, releasing CO2 to the reaction medium. Then the intermediate I undergoes an oxidative addition with acyl radical II, forming the supposed cyclopalladate Pd(III)/Pd(IV) intermediate III. Then, a reductive elimination of III affords the desired acylated product 51az, regenerating Pd(II) for a new cycle (Scheme 48). In 2016, Ranu and co-workers130 reported a very interesting protocol involving the ortho-acylation of 2-phenyl-benzoxazinone 69 and its derivatives with α-keto acids 1 via the palladium-catalyzed decarboxylative cross-coupling. The reaction proceeds using an excess of glyoxylic acid 1 (3 equiv) in the presence of Pd(OAc)2 (10 mol %), AgNO3 (1 equiv), and (NH4)2S2O8 (2 equiv) in DCE as the solvent. A total of 38 monoacylated 2-phenyl-benzoxazinone derivatives 51 were prepared from alkyl-, heteroaryl-, or aryl-substituted glyoxylic acids 1 in 32−86% yields after 18 h of reaction at 50 °C. Good results were obtained starting from the recalcitrant alkyl AF

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Scheme 47. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of 2-Phenylpyridine at Room Temperature

Scheme 48. Mechanism of the Pd(II)-Catalyzed ortho-Acylation of 2-Phenylpyridine

AG

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Scheme 49. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of 4H-Benzo[d][1,3]oxazin-4-one

In 2018, Xie and co-workers131 have disclosed a selective Pd-catalyzed, silver-promoted, decarboxylative acylation of unsymmetrical 1,2,3-triazoles 71 with α-keto acids 1, obtaining N-3-ortho-acylated 1,4-disubstituted 1,2,3-triazoles 51 in moderate to very good yields. The optimal reaction condition involves the stirring of a mixture of 1,2,3-triazole 71 and the αketo acid 1 (2 equiv) in the presence of K2S2O8 (1 equiv) as the oxidant and Ag2O (2 equiv) as base, using a 1:1 mixture of 1,4-dioxane and AcOH as the solvent, at 150 °C for 12 h. By using these standard conditions, 25 differently substituted N-3-

that the reaction does not involve free radical intermediates. From this observation, a plausible mechanism was proposed, which starts by the ortho-palladation of the benzoxazine 69a, forming the intermediate palladacycle(II) I. Once formed, I undergoes a transmetalation with the silver acyl intermediate II, formed by the silver-mediated decarboxylation of PGA 1a, to give intermediate III. Then, a reductive elimination occurs to form the desired monoacylated benzoxazinone 51kz and Pd(0), which is oxidized to Pd(II) for a new reaction cycle (Scheme 51). AH

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Scheme 50. Pd(II)-Catalyzed Decarboxylative Di-ortho-acylation of 4H-Benzo[d][1,3]oxazin-4-one

Scheme 51. Reaction Mechanism of the Pd(II)-Catalyzed Decarboxylative ortho-Acylation of 4H-Benzo[d][1,3]oxazin-4-one

defficient α-keto acids 1 was more evident in those bearing strong electron-withdrawing groups, with products 51md (R = 4-CF3) and 51me (R = 3-NO2) being obtained in 76% and 60% yields, respectively. In this work, there is no mention of the reaction using aliphatic or heteroaromatic glyoxylic acids 1. With respect to the 1,2,3-triazole counterpart 71, it was observed that the electronic density of the pendent phenyl group of C-4 does not seem to influence the reactivity of the substrate, and products 51mf−mj were obtained in around the

o-acylated 1,2,3-triazoles 51 were obtained in 47−89% yields, with high regioselectivity (Scheme 52). In general, the methodology demonstrated a good suitableness to arylsubstituted glyoxylic acids 1, with the better results being obtained starting from electron-rich ones. For example, 51lx (R = 4-CH3) and 51ly (R = 4-OMe) were isolated in 89% and 83% yields; meanwhile, the electron-poor derivatives 51lz (R = 4-F) and 51ma (R = 4-Cl) were obtained in 75% and 77% yields, respectively. The dropping in the reactivity of electronAI

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Scheme 52. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of 1,4-Disubstituted 1,2,3-Thiazoles

In 2016, Cui, Wu, and Chen132 reported a Pd(II)-catalyzed decarboxylative ortho-acylation of quinoline-N-oxides 72. The optimal procedure involves the use of 2 equiv of α-keto acid 1 in the presence of PdCl2 (10 mol %) as the catalyst and K2S2O8 (2 equiv) as an oxidant and DCE as the solvent at 80 °C for 24 h. This methodology presented a high selectivity to the acylation only on the C-8 of the quinoline-N-oxide 72, with no C-2 acylated product being observed, as previously demonstrated by Muthusubramanian and co-workers63 through a Ag(I)-catalyzed approach (see Scheme 11, section 3.1.1). By this protocol, 20 different C-8 acylated quinoline-Noxide derivatives 51 could be obtained in poor to excellent yields, presenting a very good tolerance to electron-donor and electron-withdrawing substituents on the substrates. Regarding the para- and meta-substituted aromatic α-keto acids 1, a remarkable decrease in the reaction efficiency was observed when electron-donor and electron-withdrawing groups were present in the phenyl ring, with the respective products 51cw−db being obtained in a range of 60% to 83% yield vs 95% yield of 51cw, the product from unsubstituted (neutral) PGA 1a. It is worth mentioning that the brominecontaining products 51cz and 51db could be synthesized, even in moderate yields, opening a horizon for further transformations through metal-catalyzed cross-coupling protocols. Excellent results were obtained starting from ortho-substituted α-keto acids 1, indicating that the protocol was not influenced by steric effects, and C-8 acylated products 51dc (R = 2-CH3) and 51dd (R = 2-F) were isolated in 95% and 92% yields,

same yield range (70−81%). On the other hand, the presence of substituents only in the phenyl ring connected to N-1 negativelly affects the reaction, and compounds 51mk (R = 2Cl), 51 mL (R = 3-Br), and 51 mm (R = 4-OMe) were obtained in 47%, 50%, and 62% yields, respectively. Triazoles containing N-1-benzyl groups were suitable substrates for the reaction, and compounds 51mn (R = 2-Br) and 51mo (R = H) could be isolated in 60% and 69% yields, respectively (Scheme 52). In the series of control experiments performed with the aim of elucidating the reaction mechanism, the authors have observed that the reaction was not affected by the addition of radical scavengers (TEMPO or BHT), indicating that no radical mechanism was involved in the reaction pathway. Besides, the KIE study involving the reaction between a mixture of 71a and deuterated [D5]-71a with PGA 1a showed a kinetic isotopic effect (κH/κD) of 2.6, indicating that the C−H bond cleavage is the rate-determining step. Based on these observations, a mechanism was proposed involving, in the first step, the formation of the five-membered palladacycle I, from the interaction of Pd(II) and N-3 of triazole. Once formed, intermediate I reacts with acylsilver species II, which was generated by the reaction of PGA 1a with Ag2O by releasing CO2 to the reaction medium, to afford intermediate III. Then, a reductive elimination produces the o-acylated product 51lw and Pd(0) that, after oxidation by S2O82−, regenerates the Pd(II) species for a new reaction cycle (Scheme 53). AJ

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Scheme 53. Reaction Mechanism of the Pd(II)-Catalyzed Decarboxylative o-Acylation of 1,4-Disubstituted 1,2,3-Thiazoles

Scheme 54. Pd(II)-Catalyzed C-8 Regioselective Acylation of Quinoline-N-Oxides

respectively. There is no information on the reactivity of alkyl or heteroaryl glyoxylic acids, once they were not used as substrates under these conditions. Additionally, differently substituted quinoline-N-oxide 72 derivatives were satisfactorily used as substrate in the reaction, affording the respective products 51de−dh in good to excellent yields, highlighting the presence of the methoxy group in the 5-position (R = 5-OMe), providing the respective product 51dh in 90% yield. In contrast to that observed for the α-keto acid counterpart 1, steric hindrance of the C-7 substituent of the quinoline-N-

oxide 72 caused a decrease in the yield of the respective product 51di, which was obtained in only 35% yield (Scheme 54). Based on previous reports and in control experiments conducted by the authors to elucidate the reaction pathway, a plausible reaction mechanism was proposed. Initially, the palladacycle intermediate I is formed by the C−H activation reaction between the Pd(II) catalyst and the substrate 72a, which through an anion exchange pathway with the PGA 1a is converted to the intermediate II. Following, the decarboxAK

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Scheme 55. Mechanism of the Pd(II)-Catalyzed C-8 Regioselective Acylation of Quinoline N-Oxides

step to form the palladacycle intermediate I, which is in equilibrium with intermediate II, formed by the anion exchange of TFA− with PGA−. Decarboxylation of intermediate II gives III,that undergoes a reductive elimination to form the desired product 51dj and Pd(0). Ammonium persulfate assists in the palladium reoxidation step in the catalytic cycle (Scheme 57). A closely related work was described by Kim and coworkers, which have used phenylacetamides 74 instead of acetanilides 73 as a directing group in the ortho-acylation of arenes with α-keto acids 1.137 The obtained products are important core motives, present in many bioactive molecules and widely used as building blocks in organic synthesis.138,139 By using the same catalyst/oxidant system used by Ge and coworkers,136 17 different benzacetamide derivative ketones 51 were prepared in 37−75% yields after 20 h at 70 °C in DCE as the solvent. Interestingly, the authors were able to selectively prepare mono 51 or bisacylated benzacetamides 75, just by controlling the amounts of α-keto acid and (NH4)2S2O8. Thus, when 3 equiv of PGA 1a and of persulfate were used, it was possible to drive the reaction to the bisacylated products 75a− c starting from symmetrical phenylacetamides. The exception was that substituted with the strong electron-withdrawing CF3 group, which afforded the monoacylated derivative under these conditions. Nonsymmetrical acetamides, in turn, favor the monoacylated arenes, with good outcomes for both ortho- and meta-substituted phenylacetamides 75 (Scheme 58). To show the synthetic utility of the prepared compounds, the monoacylated benzacetamide 51ej was converted to the 3isochromanone 77 in two steps: a reduction with NaBH4 followed by an intramolecular cyclization of the alcohol intermediate 76, with an overall yield of 72% (Scheme 58). The authors have proposed a mechanism for preparation of the monoacylated benzacetamides 51, which involves palladacycles like I and II, as shown in Scheme 57.

ylation of the complex II affords the intermediate III, that after a reductive elimination releases the coupling acylated product 51cw and Pd(0). Finally, Pd(0) can be oxidized by K2S2O8, regenerating the Pd(II) catalyst in the reaction medium, in order to initiate a new reaction cycle (Scheme 55). 3.1.3.2. Amides and Carbamates as Directing Groups in o-Acylation Reactions. The structural motif acetanilide has received great attention in synthetic organic chemistry as a directing group to promote ortho-C−H bond activation in arenes, leading to the formation of new C−C bonds.112−116,133 The resulting o-acyl acetanilides are important synthetic intermediates in the synthesis of bioactive natural compounds and have presented themselves interesting pharmacological activities.134,135 Ge and co-workers136 reported, in 2010, the Pd-catalyzed decarboxylative ortho-acylation of acetanilides 73, using (NH4)2S2O8 as oxidizing agent. A total of 39 differently functionalized o-acyl acetanilides 51 were obtained by stirring a mixture of acetanilide 73 and α-keto acid 1 (2−3 equiv) in the presence of Pd(TFA)2 (1.0 mol %) and (NH4)2S2O8 (2 equiv) in diglyme as the solvent for 7−48 h at room temperature (Scheme 56). Apparently, the method was not sensible to electronic effects of substituents both at the para- and orthopositions in the aryl-substituted glyoxylic acids 1, as shown for diaryl ketones 51dk−dr. Very good results were obtained when aliphatic α-oxocarboxylic acids were used, as for products 51ds−du. Regarding the acetanilide counterpart, the presence of electron-donor groups positively affects the reaction, compared to the electron-withdrawing ones. This effect is more remarkable for m-substituted acetalinides, for which the reaction does not work well. When o-substituted acetanilides were used, the reaction failed completely. The method was successfully extended to other aryl amides, like pyrrolidin-2one (51eg, 80% yield) and urea derivatives (51eh, 61% yield). The proposed catalytic cycle for this reaction was similar to that shown in Scheme 46, with the o-palladation as the first AL

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Scheme 56. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Acetanilide under Mild Conditions

Saxena and co-workers have described the use of [Fe(III)(EDTA)η 2 -O 2 ] −3 as an oxidizing species instead of (NH4)2S2O8, and Pd(OAc)2 was the catalyst instead of Pd(TFA)2 in the o-acylation of arenes.140 The Saxena protocol showed to be more general, and the reaction was faster than that previously reported by Ge.136 A variety of diaryl ketones and other acylated heterocycles were prepared in good to excellent yields in 10−30 min of reaction at room temperature in water. The good performance of the reaction system was attributed to the dual role of the iron peroxo complex as an electron-transfer-mediated oxidant and a phase-transfer catalyst. Other oxidants, like (NH4)2S2O8, K2S2O8, H2O2, and TBHP, were not so efficient in the reaction, probably due to the low solubility of the substrates in water. The optimized conditions involve the use of Pd(OAc)2 as a catalyst (1−2 mol %) and [Fe(III)EDTA-(η2-O2)]−3 (1.0 equiv) as an oxidant in water (60 mmol of H2O/mmol of acetanilide 73), and it was extended to several acetanilides with good yields in almost all the examples (Scheme 59). The more recalcitrant 3indolylglyoxylic acids reacted with acetanilide 73a to afford the respective cross-coupled products 51fa−fc in moderate yields. However, yields were increased to up 92% using 2.0 equiv of [Fe(III)EDTA-(η2-O2)]−3 and 4 mol % of Pd(TFA)2

instead of Pd(OAc)2. The catalyst iron peroxo complex is prepared in situ by the reaction of Fe(III)EDTA with 33% H2O2 in the presence of 0.01 N aqueous NaOH. In order to expand the methodology, the authors performed the ortho-acylation of pyrrolidin-2-one (78) and phthalimidederived enamides 79, and excellent yields were obtained of the desired diaryl ketones 51. Even the 2-phenyl substituted was a good substrate for the reaction, affording the expected ketone 51fe in 78% yield after 30 min of reaction (Scheme 60). The versatility of the protocol was showed by the acylation of a diversity of heteroarenes, such as benzothiazole 37, benzoxazole 38, 1H-benzimidazole 80, and N-acetylbenzimidazole 81, and 2-acylated products 37−38, 80, and 81 were obtained in very good to excellent yields after 18−28 min of reaction. The authors have investigated the selectivity of the decarboxylative acylation of N-acylated indoles 84a−c and observed a good selectivity for the 3-acylated products 86a−c in overall yields (85 + 86) of 86−87% (Scheme 60). The Saxena protocol was successfully extended to 4chromene-derived acetamides 87. The respective 3-acylated chromenes 88 were selectively obtained in very good yields, regardless of the presence of electron-donor or electronwithdrawing groups at the aromatic ring of the starting AM

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Scheme 57. Mechanism of the Pd(II)-Catalyzed o-Acylation of Acetanilides

detect radical intermediates aiming to understand the mechanism of the reaction. Two concomitant catalytic cycles, one involving Eosin Y/light and the other the palladium salt, are operating (Scheme 63). First, Eosin Y is excited by light to EosinY*, which is responsible to oxidize PGA 1a to benzoyl radical I, which was trapped with TEMPO to give the adduct II, together with the Eosin Y anion radical. Then, a SET from Eosin Y·− to molecular oxygen regenerates Eosin Y for a new cycle and forms superoxide anion radical O2·−(III), which was detected by ESR. The Pd-catalyzed cycle is initiated by the opalladation of acetanilide 73a to form the palladacycle IV that couples with benzoyl radical I to form the Pd(III) intermediate V. Then, the superoxide anion radical III receives one electron from V, giving the Pd(IV) intermediate VI and peroxide anion O2−2 that reacts with two protons of the medium to form hydrogen peroxide. Finally, VI undergoes a reductive elimination to deliver the desired product 51dj and regenerates Pd(OAc)2 for a new catalytic cycle. In 2016, Chu, Sun and co-workers142 reported a Pd(II)catalyzed decarboxylative acylation of N-acetyl-1,2,3,4-tetrahydroquinolines 89 with aryl-substituted glyoxylic acids 1, to give the respective 8-acylated N-acetyl-1,2,3,4-tetrahydroquinolines 51. The best reaction condition was defined as using an excess of α-keto acid 1 (2 equiv) in the presence of Pd(TFA)2 (10 mol %) as catalyst and (NH4)2S2O8 (3 equiv) as an oxidant, using DCE as solvent at room temperature for 10 h. By this protocol, the authors have synthesized 16 acylated N-acetyl1,2,3,4-tetrahydroquinolines 51 in good to excellent yields, with an excellent tolerance to different electron-donor and electron-withdrawing substituents (Scheme 64). In general, there was no apparent electronic effects in the reactivity, and α-keto acids 1 with both electron-donor and

chromene 87. Under the optimized conditions, the less reactive 3-indolylglyoxylic acid afforded the expected highly functionalized unsymmetrical ketone 88g in 72% yield after 22 min of reaction at room temperature (Scheme 61). According to the authors, a plausible mechanism for this reaction involves the o-palladation as the first step, with the formation of an intermediate like I (see Scheme 57). The iron peroxo complex [Fe(III)(EDTA)η2-O2]−3 acts as an electron transfer mediator (ETM) assisting the reoxidation of palladium in the catalytic cycle, similar to the way (NH4)2S2O8 does in the reaction of Scheme 57. More recently, Wang and co-workers141 developed a more general and greener protocol for the ortho-acylation of acetanilides 73, using molecular oxygen as the oxidant and Eosin Y and Pd(OAc)2 as a dual catalytic system. The use of Eosin Y (3 mol %) as a photoredox catalyst in the presence of 3 W of green LED allows the use of O2 instead of stoichiometric or overstoichiometric amounts of oxidants. By this procedure, authors were able to prepare 32 differently substituted o-acylated acetanilides 51 in good yields at mild conditions (15 h at room temperature). The method showed to be not sensible to electronic effects both in the aromatic ring of the aryl-substituted glyoxylic acid 1 and in the acetanilide 73 counterpart. The method was successfully applied to alkyl derivatives pyruvic acid 1u and 4-methyl-2-oxopentanoic acid 1l. An advantage of this protocol over the o-acylation of acetanilides described so far in this review (Schemes 56−61) is its suitability to o-substituted substrates, and diaryl ketones 51fp and 51fq were obtained 82% and 77% yields, respectively (Scheme 62). The authors have conducted control experiments with a radical scavenger and used electron spin resonance (ESR) to AN

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Scheme 58. Pd(II)-Catalyzed Decarboxylative Mono- and Di-ortho-acylation of Phenylacetamides

electron-withdrawing groups afforded the expected products 51fr−fw in very good to excellent yields. For example, the electron-defficient nitro-containing derivatives 51fw (R = 4NO2) and 51fy (R = 3-NO2) were obtained in 82% and 92% yields, respectively, while 51ft (R = 4-OMe) and 51fx (R = 3CH3) were isolated in 85% and 93% yields. The method was restricted to aromatic glyoxylic acids (phenyl and naphthyl), with 2-thienyl- and 2-furylglyoxylic acids being unreactive under the optimal conditions. Satisfactorily, para-substituted N-acetyl-1,2,3,4-tetrahydroquinolines 89 were suitable substrates in the protocol, and the respective products 51fz−gb were obtained in 85 to 95% yield, with both electron-donor and electron-withdrawing groups. A slight decreasing in the reaction efficiency was observed starting from meta-substituted N-acetyl-1,2,3,4-tetrahydroquinolines 89, and products 51gc and 51gd were obtained in 80% and 70% yields, respectively, demonstrating that some effect related to steric hindrance

could be affecting the reaction efficiency (Scheme 64, selected examples). When TEMPO (a radical scavenger) was added to the reaction, no product was observed. Additionaly, the authors observed an increase in the reaction rate when the reaction was irradiated with an 18 W CFL. These observations indicated that radical intermediates could be involved in the reaction. In the light of these outcomes and supported by the literature, a plausible mechanism was proposed, which involves initially the coordination of the substrate 89a with the Pd(II) catalyst, through a C−H activation pathway, giving the palladacycle intermediate I and releasing TFA. Following, in the presence of the acyl radical species II, intermediate I undergoes an oxidative addition in the coordination sphere of the palladium, affording the intermediate III. Finally, a reductive elimination pathway releases the respective product to the reaction AO

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Scheme 59. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Acetanilides under Mild Conditions

respectively. The electron-deficient analogues 90j (R = 6-F) and 90k (R = 6-CF3) were isolated in slightly lower yields of 77% and 75%, respectively (Scheme 66). The acylation−cyclization one-pot sequence was applied by the authors in the synthesis of a small-molecule HBV inhibitor 91, through the reaction between PGA 1a and 4chloroacetanilide 73b. The expected product 13 was obtained in 85% yield, using essentially the same conditions of Scheme 66, and according the authors, this protocol has advantages over the previous methods to prepare this molecule, including readily available starting materials, higher atom efficiency, and consequent reduction of wastes (Scheme 67). Based on previous publications, authors have proposed a plausible reaction mechanism which initially describes a C−H activation pathway, by the chelation of Pd(II), leading to the intermediate I. Parallelly, the PGA 1a undergoes visible-lightmediated oxidative decarboxylation, reaching the acyl radical intermediate II that is coordinated to the Pd(II) coordinating sphere to give the intermediate III. Subsequently, through a reductive elimination pathway, the palladium catalyst is recovered, and 8-acylated N-acetyl-1,2,3,4-tetrahydroquinoline 51fr is formed. Finally, an intramolecular aldol condensation in 51fr, promoted by DBU, drives the formation of the desired product 90l, by a sequential deprotonation−protonation and dehydration steps, via intermediates IV and V (Scheme 68). In 2017, Wang and co-workers144 have disclosed the use of PGA 1 and its derivatives as acylating agents in the first example of Pd-catalyzed decarboxylative ortho-acylation of tertiary benzamides 92 through an O-coordination pathway. This protocol solves some problems usually faced in transitionmetal-catalyzed o-acylation of tertiary amides, caused by the weakness of the O-coordination interactions and electron deficiency of the aromatic ring. After an exhaustive optimization study promoted by the authors, the best reaction condition was settled as stirring a mixture of benzamide 92 and aryl-substituted glyoxylic acid 1 (2 equiv) in the presence of Pd(OAc)2 (10 mol %) as the catalyst, K2S2O8 (2.0 equiv) as

medium, regenerating the Pd(II) catalyst, in order to restart a new reaction cycle (Scheme 65). More recently, Chu and co-workers143 described the use of visible light to promote the decarboxylation of α-keto acids 1 to afford the key acyl radical for the Pd(II)-catalyzed orthoacylation of N-acetyl-1,2,3,4-tetrahydroquinolines 89. After the completion of the acylation step (10 h at room temperature), DBU was added to the mixture containing the preformed 8acylated N-acetyl-1,2,3,4-tetrahydroquinoline 51 intermediate and was stirred at 80 °C for an additional 5 h, generating the respective 4-aryl-2-quinoline derivatives 90 in good to very good yields. The first step of this one-pot acylation−cyclization consists of the irradiation (25 W blue LED) of a mixture of Nacetyl-1,2,3,4-tetrahydroquinolines 89 with α-keto acids 1 (1.5 equiv) in the presence of Pd(OAc)2 (10 mol %) as the catalyst, using DCE as the solvent for 10 h at room temperature. After this time, DBU (5 equiv) was added to the reaction vial, and the cyclization pathway was conducted at 80 °C for 5 h, affording a diversity of 24 new 4-aryl-2-quinolinone 90 derivatives, in good to excellent yields. Among the synthesized products 90, some important trends could be observed. α-Keto acids 1 bearing electron-donating groups were good substrates under the optimal conditions, affording the respective products 90a (R = 4-CH3) and 90b (R = 4-OMe) in 91% and 87% yields, respectively. On the other hand, a slight decreasing in the reaction yield was observed in the experiments using electron-deficient α-keto acids 1. For example, 90c (R = 4-F) and 90d (R = 4-NO2) were isolated in 80% and 81% yield, respectively. Products derived from o-substituted α-keto acids were obtained in good yields under the optimal conditions, and 90e (R = 2-CH3), 90f (R = 2-F), and 90g (R = 2-Br) were obtained in 78%, 75%, and 79% yields, respectively. These outcomes indicate that steric factors are more important than electronic ones in the reaction. A similar electronic effect was observed in the 6-substituted N-acetyl-1,2,3,4-tetrahydroquinoline counterpart 89, and products 90h (R = 6-CH3) and 90-i (R = 6-OMe) were obtained in 87% and 88% yields, AP

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Scheme 60. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Several Aromatic Systems under Mild Conditions

position, were the only obtained isomers, isolated, respectively, in 66% and 58% yields. In addition, N-cyclic benzamides 92 were successfully used as subtrates in the reaction with PGA, yielding the respective acylated piperidine (51jw), morpholine (51jx), and pyrrolidine derivative (51jz) in 37%, 47%, and 70% yields, respectively. It is important to highlight that pyruvic acid 1u failed completely in the reaction under the optimal conditions described above. However, acceptable yields of compounds 51jt−jv (35−47%) were obtained after some adjustments in the reaction conditions, i.e., the use of Na2S2O8 as the oxidant instead of K2S2O8, the addition of AgOAc (50 mol %) to the reaction medium, and an extended reaction time of 48 h at 100 °C (Scheme 69, selected examples). When secondary benzamides 93 were used under the optimized reaction conditions, isoindolinones 94 could be obtained in moderate yields (40−52%), through an intramolecular cyclization of the o-acylated intermediate formed in situ. The yields of the cyclized products 94a−f could be

the oxidant, TfOH (20 mol %) as an additive, and DCE as the solvent, at 70 °C for 24 h. Under these optimal conditions, 33 acylated tertiary benzamides 51 were obtained in poor to good yields. The developed protocol was not sensitive to electronic effects caused by the presence of electron-donating or electronwithdrawing groups at the phenyl ring of the aryl-substituted glyoxylic acid 1 in the reaction with N,N-dimethylbenzamide 92a, yielding the respective products 51iz−jh in a range of 60−75% yields. Equally good results were obtained using metaand ortho-substituted phenylglyoxylic acids (51jd−jh), without any remarkable decrease in the reaction yields. The versatility of the protocol was shown using benzamides 92 differently substituted, both in the phenyl ring or in the nitrogen. Again, electronic effects did not influence the reaction, and electronrich or electron-poor benzamides afforded similar average yields. An excellent regioselectivity was found starting from meta-substituted benzamides 92 in the reaction with PGA 1a. For example, compounds 51jm (R = 3-CH3) and 51jn (R = 3Cl), containing the benzoyl group at the less hindered oAQ

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Scheme 61. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Chromenes under Mild Conditions

Scheme 62. Pd(II) and Eosin Y as a Dual Catalytic System in the Decarboxylative ortho-Acylation of Acetanilides

improved to a range of 60−82%, replacing TfOH by TsOH (20 mol %), which may be related to the better capacity of TsOH in catalyzing the cyclization step as a Bronsted acid

(Scheme 70). Moreover, in order to demonstrate the synthetic applicability of the synthesized o-acylated benzamides, 2benzoyl-N,N-dimethylbenzamide 51iz was submitted to few AR

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Scheme 63. Mechanism of the Pd(II) and Eosin Y as a Dual Catalytic System in o-Acylation

Scheme 64. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of N-Acetyl-1,2,3,4-tetrahydroquinolines under Mild Conditions

AS

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Scheme 65. Mechanism of the Pd(II)-Catalyzed Decarboxylative o-Acylation of N-Acetyl-1,2,3,4-tetrahydroquinolines

Scheme 66. Visible-Light-Induced Decarboxylative ortho-Acylation/Intramolecular Cyclization of N-Acetyl-1,2,3,4tetrahydroquinolines

Scheme 67. Synthetic Application in the Preparation of an HBV Inhibitor

AT

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Scheme 68. Reaction Mechanism of the Visible-Light-Induced Decarboxylative o-Acylation/Cyclization

product 51iz and release a Pd(II) species for a new reaction cycle (Scheme 71). Carbamates are a class of compounds with an important role in the contemporary medicinal chemistry, present in the structure of several drugs and prodrugs. The wide range of applicability of these skeletons is closely linked with their high capability to overcome cell membranes.145 Inspired by the importance of carbamates in medicinal chemistry and in the recent developments in decarboxylative couplings involving αketo acids 1, Kim and co-workers reported in 2013 the Pdcatalyzed o-acylation of O-phenyl carbamates 99.146 The authors have prepared 22 monoacylated carbamates 51 in 38−76% yields, through the reaction of carbamates 99 with aryl-substituted glyoxylic acids 1 (2.0 equiv) in the presence of (NH4)2S2O8 (1.5 equiv), Pd(OAc)2 (5 mol %) as catalyst, and 20 mol % of triflic acid (TfOH) as a promotor, in DCE at room temperature for 20 h. The best yields (62−76%) were obtained with electron-deficient aryl-substituted glyoxylic acids 1 (R1 = CF3, F, NO2, Cl), while electron-rich (R1 = OMe, CH3) 2-naphthyl and 2-thienylglyoxylic acids afforded only modest yields of the respective monoacylated O-phenyl carbamates (38−55% yields). Regarding the carbamate counterpart 99, the presence of strong electron-withdrawing groups (NO2 and CO2Et) in the para-position of the aromatic ring leads to the complete failure of the reaction, while the ofluoro derivative gave only 40% of the respective monoacylated carbamate 51pb after 20 h at 40 °C. Despite a high selectivity for the monoacylated derivative 51 was observed in almost all the examples, and a mixture of mono- and bisacylated products in a range of 2:1 to >20:1 was obtained in some cases. For

transformations. The reduction of 51iz with NaBH4 gave the isobenzofuranone 95 in 86% yield, while the reaction of 51iz with hydrazine afforded the phthalazinone 96 in 91% yield, after 3 h. On the other hand, if 51iz is subjected to the reaction with hydroxylamine or NH4OAc/EtOH, the respective benzoxazinone 97 or isoindolinone 98 could be isolated in 70% and 86% yields after 24 h (Scheme 70, further transformations). The proposed mechanism for the o-acylation of the tertiary benzamides 92 with α-keto acids 1 shown in Scheme 71 is a result of several control experiments, which have included the use of radical scavenger TEMPO, intermolecular kinetic isotopic effect (KIE) study starting from deutered N,Ndimethylbenzamide [D5]-92a, and intermolecular competition experiments, using differently substituted aryl-substituted glyoxylic acids 1. The observation that in the presence of TEMPO only trace amounts of the expected o-acylated product 51iz were formed, together with the TEMPO-benzoyl adduct, indicates that a radical pathway is involved, as expected. The KIE study showed a κH/κD for the reaction of 92a/[D5]-92a of 2.5, hinting that the C−H cleavage could be the rate-determining step. Regarding the aryl-substituted glyoxylic acid counterpart 1, a small influence of the susbtituents at the phenyl ring in the reactivity was observed. The first step in the reaction is the formation of the dimeric five-membered palladacycle I through the C−H activation, followed by an oxidative addition of the acyl radical II, which is formed by the decarboxylative reaction of PGA 1a with K2S2O8. The formed Pd(III) or Pd(IV) adduct intermediate III undergoes a reductive elimination to deliver the expected AU

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Scheme 69. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Tertiary Benzamides

example, the reaction of PGA 1a with O-phenyl dimethylcarbamate 99a afforded a mixture of the monoacylated product 51or and the bisacylated derivative in a total yield of 68%, with a mono:bisacylated ratio of 12:1. When the diphenyl dicarbamate 100 was subjected to the reaction conditions using a 2-fold amount of the acylating PGA 1a, the catalyst, and the oxidant, the bisacylated product 51ph was obtained in 61% yield after 20 h at room temperature (Scheme 72). The proposed mechanism of the reaction involves first the anion exchange between Pd(OAc)2 with TfOH, affording the more electrophilic species Pd(OTf)2, which reacts with the carbamate 99a to give the palladacycle intermediate I, via opalladation. Following, PGA 1a reacts with intermediate I, releasing TfOH, to form the Pd(II) intermediate II, which loses CO2 to give intermediate III. Intermediate III undergoes then a reductive elimination to give the product 51or and Pd(0), which is reoxidized to Pd(II) by (NH4)2S2O8 (Scheme 73).146 Recently, Wang and co-workers147 have disclosed the Pd(II)-catalyzed decarboxylative ortho-acylation of C−H sp2 bonds using carbamates 99 as a removable directing group and α-keto acids 1 as acylating agents. This approach involves the stirring of a mixture of 99 and aryl-substituted glyoxylic acid 1 (1.8 equiv) in the presence of Pd(OAc)2 (10 mol %) as the catalyst, (NH4)2S2O8 (2 equiv) as the oxidant, and p-

toluenesulfonic acid (PTSA, 0.75 equiv) as an additive in DCE as the solvent at 45 °C for 24 h. Under these conditions, a diversity of 36 ortho-acylated aniline carbamates 51 were obtained in poor to very good yields. The study of the reaction scope showed that it was not sensitive to electronic effects caused by substituents in the aryl group of the α-keto acids 1, in either para-, meta-, or ortho-positions, and the products 51pi−pv were obtained in 42−71% yields. Nevertheless, it is worth mentioning that the presence of the electron-donor methoxy group caused a decrease in the reactivity, and it required heating at 60 °C to obtain the products 51pk (R = 4OMe) and 51po (R = 3-OMe) in 42% and 50% yields, respectively. Additionally, 4-iodo-phenylglyoxylic acid 1 was well tolerated, affording 51pm in 42% yield, which enables further transformations through metal-catalyzed cross-coupling approaches. A study regarding the influence of the pendent groups at the phenyl ring of the aniline carbamates 99 in the reaction with PGA 1a revealed that para-substituted substrates were not clearly influenced by electronic effects. For example, the acylated carbamates 51pz (R = 4-CH3) and 51qb (R = 4F) were obtained in 53% and 58% yields, respectively. In the case of meta-substituted ones, however, the presence of strong electron-withdrawing groups (R = 3-CF3 or 3,4-Cl2) required higher temperature (60 °C) to afford the respective products 51qi and 51qj in 45% and 53% yields. A similar increase in the AV

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Scheme 70. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Secondary Benzamides and Synthetic Applications of the Developed Methodology

temperature to 60 °C was necessary to prepare the iodinecontaining derivative 51qh (R = 3-I) and the O-substituted carbamates 51qk (R = C2H5) and 51ql (R = C6H5), which were obtained in 61%, 70%, and 61% yields, respectively (Scheme 74, selected examples). The proposed mechanism of the reaction starts with a orthopalladation of the substrate 99b by the Pd(II) catalyst, forming the six-membered palladacycle I, which in the presence of the acyl radical II, generated from the decarboxylation of 1a promoted by the (NH4)2S2O8, undergoes an oxidative coupling, affording the Pd(III) intermediate III. Subsequently, a further oxidation gives the Pd(IV) intermediate IV, which finally undergoes a reductive elimination, releasing the desired product 51pi to the reaction medium and regenerating the Pd(II) catalyst to a new reaction cycle (Scheme 75). Methyl (2-benzoylphenyl)carbamate 51pi and the ethyl and phenyl analogues 51qk and 51ql were chosen by the authors to demonstrate the synthetic versatility of the prepared compounds, which were transformed to valuable products by simple reactions. For example, 51pi could be directly transformed to the highly substituted indole derivative 103 in 81% yield, through an annulation with (ethoxyethynyl)-

lithium. Alternatively, the NH-free acridone 104 was obtained in 82% yield, through a Cu(I)-catalyzed intramolecular annulation and simultaneous carbamate removal. Alternatively, the NH2-free derivative 51qm, which was obtained from the carbamate removal of 51pi using KOH/H2O/MeOH or from 51qk and 51ql in the presence of TBAF/THF, was converted to 2,4-diphenylquinazoline 101 in 78% yield, by reaction with NH4OAc and the benzylic toluene C−H bond. Alternatively, the NH-free aniline 51qm can undergo an aldol condensation, followed by an intramolecular annulation, in the presence of acetone, under basic conditions, affording 2-methyl-4-phenylquinoline 102 in 92% yield (Scheme 76). 3.1.3.3. Nitrosoanilines as Directing Group in o-Acylation Reactions. N-Nitrosoanilines 105 have been efficiently used as a directing group in o-acylation reactions by the direct sp2 C− H bond activation.148−150 The nitroso group can after be transformed in other functional groups, such as amine, hydrazine, and diazonium salts, opening a number of new possible transformations.151 Wu, Luo, and co-workers152 have described the ortho-acylation of N-nitrosoanilines 105 with αketo acids 1 using the system Pd(OAc) 2 (5 mol %)/(NH4)2S2O8 (2.0 equiv) in diglyme, previously used by AW

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Scheme 71. Reaction Mechanism of the Pd(II)-Catalyzed Decarboxylative o-Acylation of Benzamides

Kim153 and by Tan154 in the o-acylation of O-methyl ketoximes and aldoximes. By reacting a series of differently substituted Nnitrosoanilines 105 with 2 equiv of α-keto acids 1 at room temperature for 18 h, the authors have prepared 29 diaryl ketones 51 in 35−94% yields. The worst performance was observed using alkyl glyoxylic acids as acylating agents, and the only successful reaction was with pyruvic acid 1u, with the methyl aryl ketone 51gv being isolated in only 35% yield. Slightly lower yields were obtained starting from o-substituted aryl-substituted glyoxylic acids, due to steric effects. There was no apparent influence of electronic effects of substituents in the aromatic ring of both the aryl-substituted glyoxylic acids 1 and the N-nitrosoanilines 105. Similarly, equally very good yields were obtained starting from different N-alkyl-substituted Nnitrosoanilines 105 (R2 = CH3, C2H5, or nBu). The 1,2,3,4tetrahydroquinoline derivative 51kh was efficiently obtained by this protocol (81%), while the indoline analogue 51ki could not be prepared in an isolable amount (Scheme 77). The proposed mechanism for the reaction of N-nitrosoanilines 105 with α-keto acids 1 is quite similar to that previously described in Scheme 70, involving the O-methyl benzaldoxime as C−H activators. The first step is the o-palladation of the Nnitrosoaniline 105a, to give the six-membered palladacycle intermediate I, which undergoes a ligand exchange with PGA 1a to form the Pd(II) intermediate II and AcOH. Following, the elimination of CO2 in the presence of (NH4)2S2O8 occurs, with the formation of the intermediate III, containing Pd(III) and/or Pd(IV), which after a reductive elimination deliver the coupling product 51ge (Scheme 78). The usefulness of the o-acylated N-nitrosoaniline 51 was demonstrated in the synthesis of the worldwide marketed anxiolytic drug Diazepam 106 and the C3-substituted indole derivative 107, starting from the chloro-substituted diaryl ketone 51kd (Scheme 79). In the first reaction, compound 51kd was reacted with Fe0 under acidic conditions to selectively reduce the NO group, affording the respective aniline, which reacts in situ with ethyl glycinate 108, to form the desired Diazepam 106 in 67% yield (Scheme 79, reaction

A). In the synthesis of indole 107, the o-acylated Nnitrosoaniline 51kd reacts with the strong base tBuOK, in order to remove a methyl proton and promote the intramolecular cyclization to the carbinol intermediate 109 in 73% yield. The reduction of 109 with Raney-Ni/H2, followed by quenching under acid conditions, afforded the desired indole 107 in 55% yield (Scheme 79, reaction B). In 2016, Wang and Yao155 have disclosed an efficient Pd(II)-catalyzed decarboxylative ortho-acylation of N-nitrosanilines 105 with α-keto acids 1. The optimal conditions involve the stirring of a mixture of the α-keto acid 1 and the Nnitrosaniline 105 (1.5 equiv) in the presence of Pd(OAc)2 (10 mol %) as the catalyst and K2S2O8 (2 equiv) as the oxidant, in dioxane/AcOH (7:3) as the solvent for 12 h at 80 °C. The desired o-acylated N-nitrosanilines 51 were obtained in moderate to excellent yields, exhibiting an excellent selectivity for the syn isomer relative to the N−N bond. Using the developed methodology, the authors have promoted the synthesis of 23 acylated N-nitrosaniline derivatives 51, studying the effect of different electron-donating and electron-withdrawing groups in the phenyl ring at different positions, in both the starting materials. Regarding the arylsubstituted glyoxylic acids 1, the best results were obtained starting from electron-defficient substrates. For example, ptolyl-glyoxylic acid (R = 4-CH3) afforded the respctive product 51kj in 78% yield: meanwhile, the best results were obtained starting from electron-deficient p-Cl and p-CF3-substituted, which afforded the respective acylated N-nitrosanilines 51kk and 51kl in 91% and 80% yields, respectively. Interestingly, para-phenyl-substituted α-keto acid was less reactive under the reaction conditions, and product 51km was obtained in 55% yield. Satisfactorily, ortho-substituted and disubstituted α-keto acids with both electron-donating and electron-withdrawing groups demonstrated an excellent suitableness to the optimal reaction conditions, giving the desired products 51kn−kq in a range of 68%−79% yields. In addition, iodine-containing arylsubstituted glyoxylic acid was successfully used as a substrate, affording the respective product 51kr in 73% yield, opening AX

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Scheme 72. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of O-Phenyl Carbamates under Mild Conditions

The reaction mechanism, according the authors, is initiateD by the ortho-palladation of the N-nitrosaniline 105a by the Pd(OAc)2 catalyst, giving the five-membered palladacycle I, that after an anion exchange with PGA 1a affords the intermediate II. The formation of the five-membered palladacylcle explains the high selectivity in favor of the syn products. Subsequently, a K2S2O8-promoted decarboxylative oxidation of the intermediate II furnishes the Pd(III) or Pd(IV) intermediate III, releasing CO2 to the reaction medium. Finally, a reductive elimination pathway regenerates the Pd(II) catalyst, in order to restart another catalytic cycle, releasing the desired product 105a to the reaction medium. The authors did not discard a parallel reaction mechanism involving a Pd(0/II) catalytic cycle (Scheme 81).

different possibilities to further transformations through metalcatalyzed cross-coupling. Electron-poor N-nitrosanilines 105 (R = 4-Cl, 3-Cl, and 4-CO2Me) were well tolerated under the optimal conditions, and the respective products 51ks−ku were obtained in 50% to 55% yields, with excellent syn to anti ratios. When the ortho-substituted N-nitrosaniline 105 (R = 2-CH3) reacted with PGA 1a, the respective product 51gs was isolated in 65% yield, however with a decrease in the selectivity (syn:anti ratio = 84:16). The same limitation was observed when the alkyl group bonded to the nitrogen atom in the Nnitrosaniline 51 (R1 = C2H5 or iBu), with the respective acylated produts 51kf and 51kv being obtained in 62% and 56% yields. The selectivity was totally lost when the alkyl group was isobutyl (Scheme 80, selected examples). AY

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Scheme 73. Reaction Mechanism of the Pd(II)-Catalyzed Decarboxylative ortho-Acylation of O-Phenyl Carbamates

Almost simultaneously, Sun and co-workers156 have reported a closely related protocol to access acylated Nnitrosanilines 51 exclusively with the configuration syn. In this case, Pd(TFA)2 (10 mol %) was used as a catalyst to achieve the ortho-acylation of several N-nitrosanilines 105 using an excess of the α-keto acid 1 (2 equiv) instead of the Nnitrosanilines 105, as in the previous work.155 The mixture was dissolved in diglyme and stirred under an argon atmosphere at 80 °C for 20 h, affording a total of 26 different o-acylated Nnitrosanilines 51 in 42−94% yields. The electronic effects in both aryl-substituted glyoxylic acids and the N-nitrosanilines were evaluated. Electron-rich and electron-deficient α-keto acids 1 were demonstrated to be good substrates under the optimal conditions, affording the respective products 51g−f, 51jz, 51kw, and 51gp in very good to excellent yields. For example, product 51gp, derived from the electron-deficient trifluoromethyl-substituted phenylglyoxylic acid (R = 4-CF3), was obtained in 89% yield. Minor limitations were found when ortho-hindered α-keto acids 1 (R = 2-F and 2-Br) and the respective products 51gl and 51gm were isolated in 76% and 73% yields, respectively. Similarly, sterically hindered mesitylglyoxylic acid 1aj was not efficient in promoting the acylation, giving the respective product 51gw in only 42% yield. Satisfactorily, heterocyclic α-keto acids 1an (2-thienyl) and 1am (2-furyl) were suitable substrates, affording 51gx and 51gy in 53% and 59% yields, respectively (Scheme 82, selected examples). Regarding the N-nitrosaniline counterpart 105, several para-substituted derivatives were evaluated and, among the obtained products 51gn, 51kx, 51ke, and 51gp, it is remarkable that strong electron-donating and electron-withdrawing groups negatively influenced the reaction compared to

other substituents. Thus, the o-acylated products 51kx (R = 4OMe) and 51gp (R = 4-CF3) were obtained in 50% and 57% yield, respectively. Finally, different N-alkyl nitrosanilines 105 were employed, affording 51gt (R = C2H5) and 51gu (R = iPr) in 86% and 64% yields, respectively; however, the selectivity was lost, and a mixture of syn and anti isomers was obtained, analogously to that observed by Wang and Yao155 (Scheme 82, selected examples). The proposed mechanism for the reaction is essentially the same as depicted in Scheme 81, for the reaction using Pd(OAc)2. Few of the synthesized products 51 were easily converted to the respective 3-aryl-indazoles 41, through the reaction with Zn (5 equiv) and AcOH (1 mL), for 24 h at room temperature. Using this protocol, nine different 3-arylindazoles 43 were obtained in excellent yields (96−99%), showing a good tolerance to the presence o electron-donor and electron-withdrawing groups in the aromatic rings (Scheme 83, selected examples). Recently, Zhang, Fan, and Wang157 disclosed a very useful approach to afford N-nitroso-2-aminobenzophenone 51, through a Pd(II)-catalyzed decarboxylative ortho-acylation of the in situ generated N-nitrosoaniline, with α-keto acids 1. In a typical procedure, a mixture of N-methylaniline 110 and the αketo acid 1 (3 equiv) in the presence Pd(OAc)2 (5 mol %) as the catalyst and t-BuONO (3 equiv) as a nitro source and also as an oxidant in DCE is stirred at 40 °C, for 20 h. A great advantage of this MCR approach in comparison with methods starting from preformed N-nitrosoamines is the fact that the prenitrosation of N-methylaniline 89 is not required, avoiding the use of strong acidic conditions as well as eliminating additional reaction steps. Once the optimal reaction conditions AZ

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Scheme 74. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Carbamates

were defined, the authors conducted a detailed study on the reaction scope, which was able to provide information about the reaction sensibility against electronic effects excerced by substituents both in the glyoxylic acids 1 and in the Nmethylaniline 110. A total of 34 different N-nitroso-2aminobenzophenone derivatives 51 were prepared in poor to excellent yields. Initially, the suitability of the α-keto acids 1, bearing electron-donating and electron-withdrawing substituents, was systematically evaluated. Satisfactorily, derivatives substituted in the ortho-, meta-, and para-positions proved to be good substrates for the reaction, once the products 51ge− 51gp were obtained in good to very good yields. Besides these good results, it is worth to mention that the electron-poor derivative 51gh, with the strong electron-withdrawing trifluoromethyl group (R = 4-CF3), was obtained 76% yield, while the bromo-containing compounds 51gg (R = 4-Br) and 51gm (R = 2-Br) were isolated, respectively, in 78% and 74% yields, amplifying the possibilities to further metal-catalyzed transformations. Additionally, the highly steric hindered mesitylglyoxylic acid 1aj as well as heteroaromatic derivatives

1an (2-thienyl) and 1am (2-furyl) were also suitable substrates, affording the respective products 51gw−gy in 66%, 68%, and 69% yields. Pyruvic acid 1u did not demonstrate the same efficiency as the aromatic analogues, giving the respective product 51gv in only 33% yield. Regarding the N-methylaniline 110a, however, the electronic effects were important, with electron-poor substrates being less reactive. For example, the electron-poor acylated product 51gp (R = 4-CF3) was obtained in 55% yield, while the electron-rich analogue 51gq (R = 3-CH3) was isolated in 79% yield. NEthyl- and N-isopropyl anilines 110b and 110c were also suitable substrates for the reaction, and the respective oacylated products 51gt (R = C2H5) and 51gu (R = iPr) were obatined, respectively, in 88% and 72% yields. Finally, the 8acylated tetrahydroquinoline derivative 51gz could be obtained in a very good yield of 85% (Scheme 84). The proposed reaction mechanism starts by the homolytic cleavage of tert-butyl nitrite, to give tert-butoxyl and NO radicals, which react with the N-methylaniline 110a to afford the N-nitrosoaniline 105. Thus, the in situ generated NBA

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Scheme 75. Reaction Mechanism of the Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Carbamates

nitrosoaniline 105 undergoes an ortho-palladation with the Pd(II) catalyst, which is assisted by the NO as a directing group, reaching the five-membered palladacycle I. After, the αketo acid 1 reacts with intermediate I, affording the intermediate II, which undergoes an oxidative decarboxylation, releasing CO2 to the reaction medium and giving the intermediate III. Finally, a reductive elimination releases the product 51ge to the reaction medium and Pd(0) that in the presence of tBuONO is oxidized to Pd(II), restarting the reaction cycle (Scheme 85). Aiming to find an all-in-one-pot reaction protocol to the synthesis of 2-aminobenzophenones 111, the authors concentrated their efforts to find a suitable reducing system to remove the NO unit from the synthesized N-nitroso-2aminobenzophenone 51, without the need to isolate and purify the intermediate. After an optimization study of the reaction, the Fe0 (4 equiv)/NH4Cl (3 equiv) system proved to be the most appropriate to promote the reducing pathway. The authors prepared 18 functionalized 2-aminobenzophenones 111 in poor to good reaction yields, after 10 h at 80 °C. A good tolerance to the presence of electron-releasing and electron-withdrawing groups in the aromatic ring of both the aryl-substituted glyoxylic acid and the aniline was observed, confirming that a very useful approach was developed (Scheme 86). The bromo-containing 2-aminobenzophenone 111g was successfully used as starting material in the synthesis of the acridinone derivative 112, which is a class of valuable derivatives for medicinal chemistry. Two approaches were employed, and the desired product could be obtained in 95% and 85% yields after an intramolecular cyclization. The robustness of the protocol was shown in the large-scale synthesis of the N-nitroso-2-aminobenzophenone derivative

51ge and the 2-aminobenzophenone derivative 111a, in a 5 mmol scale, which were accessed in 85% and 65% yields, respectively (Scheme 87). 3.1.3.4. Ketones as Directing Groups in o-Acylation Reactions. Ketones are an important directing group widely used in transition-metal-catalyzed C−H functionalization of aromatic compounds, in order to access new C−C (1,2diacylbenzenes) and C−heteroatom bonds.158 In the case of 1,2-diacylbenzenes, they are normally prepared by the deprotection of o-acylated O-alkyl ketoxime, which, in turn, can be obtained as shown previously in this review (see Schemes 88 and 89). However, the necessity of using strong N-directing groups and an additional deprotection step are important limitations of this approach. In 2017, Yu and coworkers159 reported for the first time the direct ortho-acylation of aryl ketones 51 through the palladium-catalyzed decarboxylative cross-coupling with α-keto acids 1. By this new protocol, the authors were able to prepare 19 differently substituted 1,2-diacylbenzene derivatives 113, using K2S2O8 (3.0 equiv) as an oxidant and Pd(OAc)2 as the catalyst (5 mol %) at 80 °C, under N2 atmosphere, in DCE as the solvent for 24 h. The authors have observed that better results were obtained when TFA was used as an acid additive, and the oxidant was added batchwise (3 × 1 equiv/h) (Scheme 88). Several diaryl or alkyl aryl ketones were efficiently coupled with aryl-substituted glyoxylic acids 1, with a good tolerance to substituents in both the aromatic ring and to alkyl groups connected to the carbonyl in 51. Benzophenone and symmetrically substituted derivatives reacted satisfactorily with PGA 1a to render the coupled 1,2-diacylbenzenes 113a−c in 71−84% yields with lower yields being observed for the para-substituted ones 113b−c. Aromatic ketones 51 containing alkyl groups reacted equally well with PGA, except BB

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Scheme 76. Synthetic Versatility of the Developed Methodology in the Synthesis of Different Heterocycles

turnover-limiting step. In parallel, the formation of the acyl radical II occurs, which oxidatively couples with I to give the putative Pd(III) or Pd(IV) intermediate III. Finally, the reductive elimination from III renders the desired 1,2diacylbenzene 113 and regenerates Pd(II) for a new cycle (Scheme 89). β-Carboline is an important class of natural alkaloids that plays a pivotal role in pharmacology due to its presence on the core of bioactive compounds, which presents several applications against diverse pathologies.160−164 In view of the importance of this class of compounds, Batra and Kolle165 have developed a Pd(II)-catalyzed decarboxylative acylation of βcarboline ketone derivatives 114 using α-keto acids 1 as acylating agent. The best condition for this reaction involved the stirring of a mixture of the β-carboline 114 and the α-keto acid 1 (1.5 equiv) in the presence of Pd(OAc)2 (10 mol %) as the catalyst and K2S2O8 (2 equiv) as the oxidant agent in DCE as the solvent at 80 °C for 16 h. Using these optimal conditions, 20 acylated β-carboline ketone derivatives 113 were synthesized in good to very good yields, presenting a wide range of electron-donating and electron-withdrawing substituents in the molecule. In general, the reaction was not sensitive to electronic effects in the phenyl ring of the α-keto acids 1, with a narrow difference among the yields of products 113n−r, which were obtained in 78−83% yields. Interesting to notice, the electron-poor 3-nitrophenyl glyoxylic acid (R = 3NO2) was a suitable substrate, affording the expected product 113q in 83% yield, without any modification in its structure.

in the case of acetophenone, which afforded the acylated derivative 113d in only 30% yield. This low yield was attributed to the relatively slow cyclopalladation step of acetophenone compared to the other ketones. Adamantyl aryl ketones were good substrates for this reaction, affording the expected 1,2-diacylbenzenes 113e−h in good to excellent yields. Aryl ketones o-substituted, like xanthone dibenzoheptanone, could be converted to their respective diacylated derivatives 113i−k in good yields (Scheme 88). Pyruvic acid 1u, the heteroaromatic 2-thienylglyoxylic acid 1an, and the highly hindered 2,3,4,5,6-pentamethylphenylglyoxylic acid did not react under Yu’s conditions, while 2-naphthylglyoxylic acid afforded the respective diacylated derivative in only 37% yield. When the unsymmetrically substituted benzophenone 51kw was reacted with PGA 1a, a mixture of 113l and 113m was obtained in 80% yield, with preference for the acylation in the electron-rich CH3-substituted ring (113l:113m ratio = 3.2:1). The preference for the activated ring is reasoned in terms of the rate-determining C−H palladation step, in which a partial positive charge is generated in the arene (see Scheme 89 for a mechanism proposal). The proposed mechanism of the reaction involves first the conversion of Pd(OAc)2 to Pd(TFA)2 in situ, which reacts to form the intermediate palladacycle I by the electrophilic opalladation of the arene ketone 51. An NMR study of the acylation of an equimolar mixture of benzophenone and deuterated benzophenone showed a κH/κD of 3.7, which implies that the Pd-mediated C−H cleavage to form I is the BC

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Scheme 77. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of N-Nitrosoanilines under Mild Conditions

Heteroaromatic 2-thienylglyoxylic acid 1an and the 1,3benzodioxole derivative were good acyl-transfer agents in the reaction, giving the respective products 113x and 113y in 77% and 79% yields. Unfortunatelly, the reaction failed completely when alkyl-substituted pyruvic acid 1u and 2-oxobutyric acid 1v were used as substrates. Additionally, β-carboline ketone derivatives 114, functionalized on the pendent phenyl group of the keto portion, were used as substrates, affording the products 113s−113w in good to excellent yields. Slightly lower yields were obtained starting from meta-substituted derivatives compared to the para-ones, and the acylated β-carbolines 113v (R = 3-OMe) and 113w (R = 3-Cl) were obtained in 78% and 76% yields, respectively. Also, 113s (R = 4-OMe) and 113u (R = 4-Br) gave the expected products in 87% and 84% yields. Heteroaromatic β-carboline ketone derivatives 114 (2-thienyl and 2-benzofuranyl) were efficiently acylated with PGA 1a under the optimal conditions, giving the respective products 113aa and 113ab in 87% and 74% yields. The reaction scope was extended to phenyl(pyridine-2-yl)methanone, which was converted to the product 113z in 79% yield, confirming the versatility of this approach (Scheme 90, selected examples). The usefulness of the o-acylated β-carboline ketones 113 was shown by the authors in the synthesis of β-carbolinetethered phthalazine derivatives 32, easily prepared by the annulation reaction with 1 equiv of hydrazine hydrochloride in the presence of NaHCO3. Satisfactorily, eight differently substituted phthalizides 32 were obtained in 82−92% yields in 3 h of reaction, using ethanol as the solvent at 70 °C (Scheme 91). 3.1.3.5. Azobenzene as Directing Group in o-Acylation Reactions. Another important class of nitrogen-containing compounds, which are greatly valued, mainly as an industrial

feedstock, once they are applied in dyes and as indicator, are the azo compounds.166−168 Besides, they are found in the literature as photochemical switches,169−173 in some biological processes, and as therapeutic agents.174,175 Thus, due to the important applications which these compounds have been presenting, several methodologies have been developed to obtain azo-containing compounds through different pathways.176−184 In 2013, two papers describing the Pd-catalyzed decarboxylative ortho-acylation of azobenzenes 115 with α-keto acids 1 have appeared simultaneously, one by G. Wang and coworkers185 and other authored by L. Wang and co-workers.186 In both cases, Pd(OAc)2 and K2S2O8 were used as catalyst and oxidant, respectively, and the desired products were obtained in moderate to very good yields. In G. Wang’s work, the azobenzene 115, aryl-substituted glyoxylic acid (1.1 equiv), Pd(OAc)2 (10 mol %), and K2S2O8 (2 equiv) in a mixture of dioxane/AcOH/DMSO (ratio of 7:2:1) as the solvent were stirred at 80 °C for 10 h. A total of 23 differently substituted oacyl azobenzenes 51 were obtained in 50−88% yields, including electron-rich and electron-poor substrates (Scheme 92, Method A).185 The protocols are restricted to arylsubstituted glyoxylic acids, and both appear to be insensitive to electronic effects, both in the aromatic ring of the α-keto acid 1 and in the azobenzene counterpart 115. This was demonstrated when unsymmetrical (E)-1-(4-methoxyphenyl)-2-phenyldiazene 115a was subjected to the reaction with PGA 1a; a 1:1.1 mixture of monoacylated products in the two phenyl rings 51nk and 51nl was isolated in 83% overall yield (Scheme 93).185 In the Wang’s protocol, in turn, azobenzenes 115 were coupled with 1 (1.5 equiv) using a lower load of both catalyst BD

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Scheme 78. Reaction Mechanism of the Pd(II)-Catalyzed Decarboxylative o-Acylation of N-Nitrosoanilines

Scheme 79. Synthetic Application of the Pd(II)-Catalyzed Decarboxylative o-Acylation of N-Nitrosoanilines

(5 mol %) and K2S2O8 (1.5 equiv) and DCE as the solvent.186 By this procedure, authors have prepared 21 o-acylated azobenzenes 51 in 53−85% yields after 36 h of stirring at room temperature. A longer reaction time was required when the heteroaromatic 2-thienylglyoxylic acid 1an was used as a substrate, and the respective o-acyl azobenzene 51nd was obtained in 53% yield after 48 h of reaction (Scheme 92, Mehod B). Some of the o-acylated azobenzenes 51 were submitted to an intramolecular cyclization reaction, using the system Cu2Cl2/NaBH4 in ethanol at room temperature, leading to 2-substituted indazoles 43 in excellent yields, in only 3 min (Scheme 93).186 Regarding the mechanism of the reaction, it is believed that the first step of the reaction is the opalladation of the azobenzene 115, to form a palladacycle intermediate, similarly to that previously described for reactions in the absence of silver.185,186

The same system used in the o-acylation of azobenzenes 115 (Scheme 92, Method B) was successfully used by L. Wang and co-workers in the coupling of azoxybenzenes 116 with α-keto acids 1.187 The authors have prepared 22 different monoacylated azoxybenzenes 51 in 44−82% yields after 24 h of reaction at 60 °C. In general, the presence of electronwithdrawing groups (Cl, F, CF3) in the aromatic ring of the aryl-substituted glyoxylic acid 1 positively affects the reaction, affording higher yields of the monoacylated products 51 compared to the electron-releasing ones, like MeO, tBu, or CH3. Such electronic effects were not observed in the 4disubstituted azoxybenzene counterpart 116, with similar yields being observed for electron-rich and electron-poor substrates. Despite that there are two potential ortho-C−H bonds which could be easily acylated in both aromatic rings, the reaction afforded exclusively the monoacylation in the BE

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Scheme 80. Pd(AcO)2-Catalyzed Decarboxylative ortho-Acylation of N-Nitrosoanilines

palladium-catalyzed decarboxylative ortho-acylation of azobenzenes 115 using α-keto acid 1 as the acylating agent. The synthesis of the ortho-acylated azobenzenes 51 was achieved by the irradiation (1.5 W blue LED) of a mixture of the azobenzene 115 and the aryl-substituted glyoxylic acid 1 (1.2 equiv) in the presence of Pd(TFA)2 (5 mol %) as a catalyst and 9-mesityl-10-methyl-acridinium perchlorate (PC) as the photocatalyst, in toluene at room temperature for 16 h. Under these optimal conditions, 27 o-acylated azobenzenes 51 were accessed in moderate to very good yields. In general, α-keto acids 1 bearing electron-donor and electron-withdrawing groups in the para-position presented similar results in affording the products 51mp−mr and 51oa−oc; meanwhile ortho-substituted substrates afforded the respective products 51my, 51na, and 51mz in lower yields. Electron-rich phenylglyoxylic acids 1 substituted with methoxy group (R = OMe) in both positions were less reactive, affording the products 51mr and 51na in 58% and 57% yields, respectively. The heteroaromatic 2-thienylglyoxylic acid 1an reacted with (E)-1,2-diphenyldiazene 115a to afford 51nd in 63% yields, while the alkyl-substituted pyruvic acid 1u did not react under the optimal conditions. Regarding the azobenzene counterpart 115, the para-disubstituted derivatives were well tolerated, affording the respective products 51od−og in a range of 58− 70% yields, with the carbethoxy electron-withdrawing group (R = CO2Et) causing a remarkable decrease in the reaction yield, affording 51og in 58% yield. Similar results were obtained starting from meta-substituted substrates 115 and the

aromatic ring directly connected to the NO group. Heteroaromatic 2-thienylglyoxylic acid 1an required a slightly higher temperature (80 °C) to afford the expected acylated compound 51nu in 51% yield. Alkyl 2-oxobutyric acid 1v reacted with 2-oxo-1,2-diphenylhydrazin-2-ium-1-ide 116a to afford the respective acylated azoxybenzene 51nv in 44% yield after 24 h at 100 °C (Scheme 94). The acylated azoxybenzenes can easily be converted to indazole 43, similarly to what was shown in Scheme 93 for the o-acylated azobenzenes.187 In this case, the intramolecular cyclization was conducted using Pd/C as catalyst in the presence of a H2 atmosphere. Using this strategy, six different heterocycles 43 were prepared in 96−99% yields after 2 h of reaction at room temperature (Scheme 95). The mechanism proposed by the authors is quite similar to those previously shown in this review for Pd-catalyzed oacylation of arenes, with the o-palladation of the azoxybenzene 116a being the first step of the reaction. The authors highlighted that nitrogen is better coordinating than oxygen, which explains the preference for the five-membered palladacycle I over the six-membered one. Once formed, I reacts with PGA 1a to release acetic acid and form intermediate II which, after decarboxylation, gives intermediate III. Then a reductive elimination occurs to deliver the acylated azoxybenzene 51nm and Pd(0) that is reoxidized by K2S2O8 to Pd(II), closing the catalytic cycle (Scheme 96). In 2016, Wang and co-workers188 have disclosed an efficient approach merging visible-light photocatalysis with the BF

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Scheme 81. Reaction Mechanism of the Pd(AcO)2-Catalyzed Decarboxylative o-Acylation of N-Nitrosoanilines

Scheme 82. Pd(TFA)2-Catalyzed Decarboxylative ortho-Acylation of N-Nitrosoanilines

obtained in 57% yield). The ortho-substituted azobenzenes 115 were suitable substrates for the reaction, and a slight steric effect was observed, affording the expected products 51ok (R =

respective acylated products 51oh−oj in 57−73% yields, with the presence of the electron-withdrawing group (R = Cl) causing a negative effect in the reaction (e.g., product 51oj was BG

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Chemical Reviews

Review

The reaction scope was expanded to the reaction of azoxybenzenes 116 with PGA 1a, aiming to access orthobenzoyl azoxybenzenes 51. A higher reaction time of 20 h was necessary to afford moderate to good yields of six different acylated azoxybenzenes 51. The yield range using para- and meta-substituted azoxybenzenes 116 bearing electron-releasing groups (R = CH3, OMe, and iPr) was similar, accessing the products 51nm and 51om−oo in 66−77% yield. However, the reaction was sensible to steric hindrance, and orthomethylazoxybenzene 116b afforded 51oq in only 37% yield under the optimal conditions (Scheme 98). Based on mechanistic insights provided by the authors in previous reports and additional control experiments using radical scavengers and kinetic isotope effect (KIE), a reaction mechanism was proposed. Initially, a photoexcitation of the mesityl acridinium salt photocatalyst PC generates its excited state PC*, which is oxidized by the air oxygen by a SET process to afford the PC· radical species and superoxide anion I. Thus, PGA 1a undergoes a single-electron oxidation, promoted by the PC·, affording the radical cation species II, which quickly is decomposed to the benzoyl radical III; meanwhile, the ground-state photocatalyst PC is regenerated in the reaction medium, ready to start a new reaction cycle. On the other hand, the ortho-C−H bond from the azobenzene 115a undergoes an ortho-palladation in the presence of the Pd(II) catalyst, giving the five-membered palladacycle intermediate IV, which undergoes an oxidative insertion of the benzoyl radical III, leading to the Pd(III) or Pd(IV) species V. Finally, the intermediate V undergoes a reductive

Scheme 83. Synthesis of Indazole Derivatives from 2-AcylN-nitrosoanilines

CH3) and 51ol (R = iPr) in 56% and 52% yields, respectively (Scheme 97, selected examples).

Scheme 84. tBuONO-Assisted Decarboxylative ortho-Acylation of Anilines

BH

DOI: 10.1021/acs.chemrev.8b00782 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

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Scheme 85. Reaction Mechanism of the tBuONO-Assisted Decarboxylative o-Acylation

Scheme 86. One-Pot Multistep Cascade Reaction to Afford 2-Aminobenzophenones

methyl ketoximes 117 with α-keto acids 1.153 A variety of differently substituted aromatic glyoxylic acids 1 and O-methyl ketoximes 117 were employed to prepare a total of 24 diaryl ketones 51 in 36−85% yields after 3−20 h of reaction at 70 °C in diglyme as the solvent. Overstoichiometric amounts of arylsubstituted glyoxylic acid 1 and (NH4)2S2O8 (1.5 equiv) were necessary to produce good yields of the acylated products. It

elimination, releasing the product 51mp to the reaction medium and affording a Pd(I) catalyst species, which in the presence of the superoxide anion I is oxidized to Pd(II), regenerating the catalyst to a new reaction cycle (Scheme 99). 3.1.3.6. Other Directing Groups in o-Acylation Reactions. The system Pd(OAc)2 (10 mol %)/(NH4)2S2O8 (1.5 equiv) was used by Kim and co-workers in the o-acylation of OBI

DOI: 10.1021/acs.chemrev.8b00782 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Scheme 87. Synthetic Application and Gram-Scale Synthesis Involving the tBuONO-Assisted Decarboxylative ortho-Acylation

Scheme 88. Pd(II)-Catalyzed Decarboxylative ortho-Acylation of Aromatic Ketones

Good results were also obtained starting from ortho-substituted ketoximes, despite the reaction being slower (10−20 h). In addition, aldoximes 118 were submitted to the reaction conditions, and the respective diaryl ketones 51hi−hj were obtained in 34% and 36% yields, respectively (Scheme 100). The postulated mechanism for the reaction involves as the first step the o-palladation of O-methyl ketoxime 117, except that in this case it has 5 members instead of 6.

was observed that the reaction is not sensible to electronic effects in the aromatic ring of the aryl-substituted glyoxylic acid, with good to very good yields of the expected dirayl ketones derived from tetralone O-methyl oxime 117a and several electron-rich and electron-poor aryl-substituted glyoxylic acids. When the strong electron-donating group OMe was present at the para-position of the acetophenone O-methyl oxime, however, the respective decarboxylative coupling product 51hd was obtained in only 36% yield after 6 h. BJ

DOI: 10.1021/acs.chemrev.8b00782 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

Scheme 89. Reaction Mechanism of the Pd(II)-Catalyzed Decarboxylative o-Acylation of Aromatic Ketones

experiments using the palladacycle 119, previously prepared by the reaction of the O-methyl benzaldoxime 118a with Pd(OAc)2 in TFA, in the reaction with PGA 1a. They have observed that the cross-coupling acylated product 51hu was obtained only when (NH4)2S2O8 was added in the reaction mixture (63% yield), indicating that Pd(III) and/or Pd(IV) intermediates are involved, not Pd(II) ones. Based on these findings, the authors have proposed a mechanism that starts by the formation of the five-membered palladacycle intermediate I, which undergoes anion exchange with glyoxylate to form intermediate II. Then, in the presence of (NH4)2S2O8, CO2 is released, and the acyl-Pd(III or IV) intermediate III is formed. After a reductive elimination, the coupling product 51hu is formed, with Pd(II) to a new cycle (Scheme 102). Aryl carboxylic acids and their carboxylate derivatives have been used as directing groups to ortho-acylation reactions,189−193 although they could be easily transformed to a good leaving group through some further functionalization or be decomposed by a photodecarboxylation process. In 2013, Miao and Ge194 described the ortho-acylation reaction of benzoic acid 120 and its derivatives with α-keto acids 1 through a palladium-catalyzed decarboxylative cross-coupling, assisted by Ag2CO3. Benzoic acid derivatization under the classic electrophilic aromatic substitution conditions results in meta-substituted products, but here, due to the formation of the metallacycle, the ortho-substituted acid is formed as a net result of the decarboxylative acylation (see mechanism below).The authors have prepared 24 different o-acylated

Almost at the same time, Tan and co-workers reported their findings in the ortho-acylation of O-methyl aldoximes 118 using essentially the same catalyst/oxidant/solvent system.154 As demonstrated above, diaryl ketones 51hi−hj, derived from aldoximes, were obtained in fair yields (